CHAPTER 2

REVIEW RELATED LITERATURE

PATHOPHYSIOLOGY OF DIABETES MELLITUS

Diabetes is a group of disorders characterized by elevated plasma glucose levels and

abnormal glucose metabolism. Low glucose utilization causes hyperglycemia. In most
cases, the true aetiology is still unknown. The WHO has developed several diabetes
classification schemes, the most widely accepted being the following:

Figure 2. Accepted diabetes classification schemes

TYPE 1 DIABETES MELLITUS

This type of diabetes was previously known as insulin-dependent diabetes or juvenile

diabetes. The pancreatic ß-cells are destroyed in type 1 diabetes. Several autoimmune
markers have been found in body fluids and tissues: (1) Auto-antibodies to islets (ICAs);
(2) insulin antibodies (IAAs); (3) auto-antibodies to GAD (GAD65); (4) autoantibodies to
IA-2 and IA-2ß. Type 1 diabetes mellitus is caused by an autoimmune attack on the
insulin-secreting cells of the pancreatic ß-cells. Numerous years before to clinical
diagnosis and presentation, the autoimmune process begins. The destruction must be
extensive, as just 10-20% of the volume of ß-cells is required to cover clinical signs. The
pace of ß-cell breakdown varies considerably between individuals, being quick in some
(mostly newborns and children) and often gradual in adults. Without a doubt,
environmental variables have a role in the onset of diabetes. The most prevalent causes
include viruses (rubella, coxsackie virus B, and mumps), chemicals, and, in some cases,
cow's milk (Palicka, 2002).
TYPE II DIABETES MELLITUS
The term type 2 diabetes mellitus (NIDDM) was previously used to refer to adult-onset
diabetes. It is far more common than type 1 diabetes, accounting for over 90% of all
diabetics. Patients are frequently older and have few symptoms. Insulin levels are usually
elevated, but might be normal or lowered. Obesity is widespread, and losing weight helps
hyperglycemia. The condition usually strikes after 40. Oral hypoglycemic medications and
dietary changes are the mainstays of therapy; insulin is used to treat hyperglycemia. The
new understanding type 2 diabetes mellitus is represented by two disorder categories.
The first is reduced insulin action on peripheral tissues. It's called "insulin resistance".
Insulin resistance is a reduced biological response to normal circulating insulin
concentrations and is the principal pathogenic mechanism. The second is pancreatic ß-
cell dysfunction, characterized by insufficient insulin production to overcome insulin
resistance in peripheral organs. Due to ß-cell malfunction, insulin production may be
insufficient to counteract insulin resistance. Insulin insufficiency is a common outcome.
The major reason - insulin resistance or insulin production derangement - was debated.
The evidence suggests that insulin resistance precedes insulin secretion dysfunction.
Insulin resistance often occurs 20 years before clinical symptoms. Insulin resistance is
caused by a mix of environmental and genetic factors. The most critical factors are body
weight and activity. Obesity and type 2 diabetes are intricately linked: while 60–80% of
patients with type 2 diabetes are fat, diabetes develops in less than 15% of obese
individuals. Clinical symptoms and therapeutic requirements typically improve with weight
loss and physical activity (Palicka, 2002).

GESTATIONAL DIABETES MELLITUS

Typically, gestational diabetes mellitus is asymptomatic and does not pose a threat to the
mother's life. The syndrome is related with a higher risk of neonatal morbidity,
hypoglycemia in newborns, macrosomia, and jaundice. Even normal pregnancies,
particularly in the second and third trimesters, are associated with an increase in insulin
resistance. Maintaining euglycemia requires increased insulin secretion. Gestational
diabetes develops in women who are unable to enhance insulin output. The pathogenesis
of gestational diabetes mellitus is unknown, however it may include a family history of
diabetes, obesity, problems during prior pregnancy (i.e.), and advanced mother age.
Preexisting diabetes mellitus must be detected, as it has a significantly worse prognosis
for the fetus (Palicka, 2002).

Chemical Constituents Analysis and Antidiabetic Activity Validation of Four Fern

Species from Taiwan

The Pteridophyta plant family includes the about 12,000 species known as ferns. In
several nations, certain fern species are used as food or traditional medicine to treat a
variety of diseases. Ferns predominantly contain flavonoids, alkaloids, phenols, steroids,
and triterpenoids; exhibit diverse bioactivities such as antibacterial, antiosteoporosis, and
anti-Alzheimer’s disease activity; and feature hypolipidemic and hypoglycemic activities.
Therefore, ferns constitute a key medicinal resource in ethnopharmacy.

First isolated from the bracken fern Pteridium aquilinum var., pterosin is a sesquiterpene
with a 1-indanone skeleton. The latiusculum (Pteridaceae). There have been discovered
around 31 pterosins from various fern species and have leishmanicidal, smooth-muscle
relaxing, and anticancer properties. In an animal model, pterosin A was expressed
against both type 1 and type 2 diabetes. In addition, other studies have shown that
pterosin A can improve insulin sensitivity, accelerate glucose absorption, and increase
AMPK (adenosine monophosphate-activated protein kinase) activation. Sesquiterpenes
known as pterosins are a big category and are extensively distributed in the
Dennstaediaceae and Pteridaceae families. In addition to photochemicals from C, we
identified the seasonal changes of nine pterosins, five pterosides, six lignans, three
flavonoids, six phenolics, and one carbohydrate from four fern species. In addition to N.
multiflora. Additionally, Compounds 21 through 23 were initially recognized in H. punctata.
Controls the metabolism of fatty acids and carbohydrates. Future research may perhaps
find that pterosin molecules are effective in treating metabolic illness. The outcomes also
showed that the pterosin distributions were the outcomes also showed that the pterosin
distributions werethe three aforementioned species (H. punctata, C. thalictroide, and P.
revolutum), with the exception of N. higher than the comparable distributions of the other
pterosin analogs for multiflora (Nephrolepdiaceae). Numerous triterpenes and steroids
have been identified from Nephrolepdiaceae in previous research. These results made it
very evident that N contained nonpterosin-type components. multiflora. Pterosin A may
protect pancreatic beta-cells from oxidative damage, but this is still unknown. As a result,
in insulin-secreting cells exposed to oxidative stress or lipotoxicity, the current
investigation evaluated any potential positive effects of pterosin A on cell survival and
ROS production. Through the AMPK signaling pathway, pterosin A in this study efficiently
decreased the ROS-induced cell damage in the insulin-secreting cells. According to
reports, long-term FFA therapy and pancreatic aberrant glucose metabolism can result in
mitochondrial malfunction, a progressive rise in ROS generation, and β-cell dysfunction.
One of the main pterosin compounds, pterosin A, has anti-diabetic properties as well as
safeguards against -cell harm. Pterosin A could therefore be employed as a lead chemical
in the creation of type 2 diabetic medications. The lower total glucose uptake in the body
was thought to be primarily caused by the impaired glucose transport in skeletal muscles
seen in type 2 diabetes patients. The absorption of glucose is improved by both insulin
stimulation and AMPK activity.

Phytochemical Properties and Effects of Crude Extracts of Sarabat Fiddlehead

Fern Shoots In Hyperglycemia Induced Normal Mice (Mus Musculus)

The current study revealed the phytochemical components of sarabat. The presence of
sterol, triterpene, flavonoids, alkaloids, saponins, glycosides, flavonoids, and tannin in the
samples was recognized and mentioned. The Sarabat fiddlehead fern extracts are
consistently high in saponins and sterols and can therefore be effective treatments for
hypercholesterolemia. The aqueous preparations of sarabat include glycosides as well.
Aqueous preparations of the same substances also include terpernes. The turbidity in the
ethanolic and methanolic extracts of Sarabat 1 indicates a moderate amount of alkaloids,
but the production of red precipitates indicates a moderate presence of flavonoids. The
bluish color shift in the ethanolic and methanolic extracts of Sarabat 2 indicates a
moderate presence of sterols. All contain residues of tannins, which are identified by
variations in the color of black. Overall, it can be demonstrated that methanolic extraction
produced a good increase in the amount of phytochemical components. The
aforementioned chemical components of Sarabat are similar to some of those of
Diplazium esculentum, according to Tongco et al. (2014), even though a wider range of
phytochemical components was evaluated in D. esculentum. This is in line with the
presence of phytochemical components like alkaloids, flavonoids, particularly in the
methanolic extracts, triterpenes in the aqueous extract, and phytosterols as shown. These
phytochemical components of the fern plant may work in concert to produce the desired
blood glucose lowering effect or enhance, influence, and modulate the various key
physiological processes like enzyme activity or transport of metabolites across
membranes. The crude extracts of the edible vegetable fern Sarabat (Diplazium
polypodiodes Blume and Diplazium sp) were found to include sterols, triterpenes,
flavonoids, alkaloids, saponins, glycosides, and tannins, with saponins predominating.
Likewise, the aqueous extract shows a significant amount of glycosides and triterpenes.
Alkaloids and flavonoids are also observed to be present in all solvents used, with the
methanolic solvent being more strongly noticed. Oral glucose tolerance test results reveal
that the medications had effects on mice at 30 and 60 minutes, with statistical differences
at 5% and 1% levels of significance and p-values of 0.002 and 0.02 respectively. The
results of additional analysis using the Bonferroni test showed that the mice receiving
Treatment 1 had significantly lower blood glucose levels than mice receiving Induced
Treatment or No Treatment. The glycalizide immediately began to lower the glucose level
at 60 minutes after treatment, especially when compared to Treatment 4 (low dose
sarabat extract), but its effect was only statistically comparable to Treatment 5. The
commercial medicine had a substantial effect compared to Treatment 4 at 60 minutes
after treatment, but this benefit was not sustained at 90 and 120 minutes after treatment,
as shown by the non-statistical differences in mean glucose levels between Treatments
4 and 5 of the experimental setup.

In Vitro Callus and In Vivo Leaf Extract of Gymnema sylvestre Stimulate β-cells
Regeneration and Anti-diabetic activity in Wistar Rats

G. Sylvestre leaf and callus extracts have been shown to have antihyperglycemic
properties in alloxan induced diabetic wistar rats. Our experimental data indicate that
alloxan administered intraperitoneally to Wistar rats demonstrates diabetic action. We
conclude that this investigation confirms the efficacy of G. sylvestre leaf and callus
extracts as potent herbal treatments and that they may be capable of completely restoring
pancreatic-cell activity and thus curing type I diabetes. G. sylvestre callus extract studies
have demonstrated how-cells may be produced and regenerated in vitro, which may
provide additional direction for possible IDDM medication development (Ahmed, A. et al.,
2010).

Anti-Diabetic Activity of Paspalum scrobiculatum linn. In Alloxan Induced Diabetic

Rats

The ethanolic and aqueous grain extracts of Paspalum scrobiculatum were evaluated for
their antidiabetic activity. The extracts reduced FBG in alloxan-induced diabetic rats.
Alloxan causes pancreatic cell damage by producing cytotoxic oxygen free radicals.
These radicals target pancreatic DNA, causing DNA fragmentation (Shankar et al., 2007).
After 60 minutes of administration of PS extracts to glucose-loaded normal rats (OGTT),
blood glucose levels were reduced. The decline peaked at 2 h. It found a significant rise
in blood glucose levels in the diabetic control group after 15 days of testing. The extracts
reduced fasting blood glucose levels and increased serum insulin levels in diabetic rats.
Thus, PS may exert hypoglycemic action by increasing either pancreatic secretion of
insulin from existing beta cells or its release from bound form. Another mechanism could
be PS's high fiber content. Dietary fibers help diabetics, especially type II diabetics, by
slowing down the rate of carbohydrate absorption from the intestine (Khan and Safdar,
2003). Lipoprotein lipase normally hydrolyzes triglycerides. Diabetes mellitus causes
hypertriglyceridemia by inhibiting this enzyme. Fibers lower cholesterol and triglycerides
(Anderson, 2000). Because Paspalum scrobiculatum contains a high amount of fiber, it
has a significant effect on serum lipid levels. Swanston-Flat et al. (1990) and protein loss
in tissues (Chatterjea and Shinde, 2002). The PS-treated rats had smaller body weight
differences than the diabetic control rats, possibly due to its protective effect in controlling
muscle wasting, reversal of gluconeogenesis, and proper glycemic control. The decrease
in hepatic glycogen content in diabetes (Whitton and Hems, 1975) is likely due to a lack
of insulin in the diabetic state, which inactivates the glycogen synthase system. These
results suggest that reactivation of the glycogen synthase system may be involved. Thus,
improving glycogenesis may be another possible anti-diabetic action (Maiti et al., 2004).
The diabetic control group had higher glycated hemoglobin levels. Increased non-
enzymatic and autooxidative glycosylation may link hyperglycemia and diabetic vascular
complications (Hall et al., 1984). The extracts significantly reduced glycated hemoglobin
levels, possibly due to improved insulin secretion. Previous research has shown that
phenolic compounds can help control diabetes and other diseases (Vasco et al., 2008;
Ahmad and Mukhtar, 1999). Both extracts contained phenolic compounds. Thus, PS's
beneficial effect may be due to phenolic compounds. The data shows that PS has
significant antidiabetic activity and may be useful in the treatment of NIDDM. It's also
important to do more longterm studies on chronic models to fully understand how the drug
works (Jain et.al., 2010).

Hypoglycemic Effect of Scarlet Spiral flag (Costus woodsonii) to Alloxan-Induced

diabetic mice in vivo study

It was an experimental design with the restrictions of utilizing 20 male Swiss mice as the
experimental unit; Alloxan as the diabetes-inducing agent; Scarlet Spiral Flag as the
treatment; and a week of monitoring for the onset of fasting blood sugar. The study
concluded that an ethanolic extract of Scarlet Spiral Flag (C. woodsonii) has significant
anti-diabetic activity in diabetic mice induced with Alloxan. Because it belongs to the same
genus as the insulin plant, it has a similar effect on blood glucose levels. While the mice
remained diabetic throughout the treatments, this could be due to the efficiency of the
Alloxan induction. It still showed a considerable hypoglycemia effect (Magtulis, R. et al.,
2020).

Plants Having Potential Anti-diabetic Activity

Leguminoseae, Lamiaceae, Liliaceae, Cucurbitaceae, Asteraceae, Moraceae, Rosaceae,

Euphorbiaceae, and Araliaceae are hypoglycemic plant groups. Trigonella foenum
graecum L., Momordica charantia L., Ficus bengalensis L., and Gymnema Sylvestre R.
were used to make this extract. The experiments employed a variety of methodologies.
Oral glucose tolerance tests can cause transient hyperglycemia (OGTT). The most
frequently utilized diabetic models were the streptozotocin and alloxan-induced diabetic
mouse or rat. Some writers used KK Ay mice as a model of type II diabetes with
hyperinsulinemia. The majority of studies verify the benefits of medicinal herbs with
hypoglycemic properties in diabetes control. These plant extracts' activities have been
proposed in many ways. Certain hypotheses suggest that they may enhance the
protective/inhibitory impact of plant extracts against insulinase and increase insulin
sensitivity or insulin-like activity. A reduction in the glycogenic index of carbs and a
reduction in glutathione's action are all possible strategies for improving glucose
homeostasis. All of these steps may help reduce or eliminate diabetic problems. This
review covered all anti-diabetic herbs used to treat diabetes mellitus. It displays the
hypoglycemic effects of the herbs mentioned above. They were often as strong as or
more potent than known synthetic oral hypoglycemic medications. However, many more
plantderived active compounds are unknown. More research is needed to determine the
mechanism of action of anti-diabetic herbs. These plants' toxicity should be clarified
(Chauhan, A. et al., 2010).

Nutritional and Antioxidant Potential of Fiddleheads from European Ferns

A warning should be heeded regarding the possible toxicity of ferns while considering
them as potential widely accessible veggies. A variety of poisonous substances have
been found in some fern species. Overall, the risk of potential intoxication is reasonably
reduced if fern fiddleheads are not consumed on a daily basis and are instead consumed
dried or properly cooked. This is because we previously tested the toxicity of mature leaf
extracts of all the species reported here on sheep hepatocytes at 100 gmL1 (Dvorakova,
M., 2021). Additionally, the majority of the species cultivated in Europe appear to be free
of toxicity and toxic substances (ptaquiloside and its analogs), making those potential
vegetables. As a significant source of essential fatty acids with a favorable n-6/n-3 ratio
and valuable antioxidants, fiddleheads from European ferns may benefit the human diet.
Our results might act as a guide for choosing the best fern species to be raised
economically as vegetables. Polypodium vulgare, Onoclea sensibilis, or Polystichum
aculeatu is an example of a species having a high level of total phenols, strong antioxidant
capacity, and a preferred n-6/n-3 ratio. A careful ingestion of fern fiddleheads along with
their adequate boiling or processing before eating could prevent potential poisoning, even
though the issue surrounding the probable toxicity still has to be addressed and evaluated
via more complete assays (Dvorakova, M., 2021).

Chemical and Biological Aspects of Extracts from Medicinal Plants with Anti-
diabetic Effects

Several plants have been shown to have anti-diabetic properties in both animal and
human studies. In some circumstances, the components of these plants have greater
anti-diabetic action than traditional medications. In this recipe, you'll find Albizzia lebbeck
and Aloe vera. You'll also find Amaryllis tricolor, Azadortha indica, Bauhinia thonigii, and
Caesalpinia ferrea. You'll also find Cassia fistula, Cecropia pachystachy, Cinnamomum
japonica, Cinnamomum cassia, Ficus racemosa, Momordica charantia, Moringa oleifera,
Nigella sativa, Opuntia milpa alta, Origanum vulgare, Perse research using medicinal
plants historically used to treat diabetes has shown hypoglycemic or antihyperglycemic
characteristics, validating their traditional use as anti-diabetics. The plants' antidiabetic
properties have multiple mechanisms of action. The wide range of chemical classes
suggests that different modes of action may be implicated in lowering or maintaining blood
glucose levels, such as boosting pancreatic insulin secretion or peripheral glucose
uptake. Some chemicals originating from medicinal plants may be helpful, while others
may cause hypoglycemia or even be poisonous to hepatocytes. The use of plant derived
compounds with promising qualities should be promoted in clinical practice to improve
diabetes management. One should now look into the biologically active components and
how they work so that they can make therapeutic medicines (Gushiken, L. et al., 2016).

Activity of Ethyl Acetate Extract from Chrysophyllum cainito L. Leaves in

decreasing Blood Sugar Level in Male Wistar Rats

The percentage drop in blood sugar level was based on the antidiabetic activity test of
ethyl acetate extract of C. cainito leaves. All treatment groups' blood glucose levels
reduced significantly over 7, 10, and 14 days (p 0.05). On day 3, all treatment groups
demonstrated a substantial decrease in blood glucose (p > 0). After that, the data is
subjected to an LSD Pos Hoc test.Table 3 shows the LSD Pos Hoc test results. Except
for P1, all groups differed significantly from the negative control group based on LSD
findings on H3. In H7, H10, and H14, all groups differed from the negative control group.
So all the extracts are anti-diabetic. These findings are supported by the fact that all group
extracts have antidiabetic efficacy when compared to negative controls. In all dose
groups, C. cainito leaves extract lowers blood sugar levels better than the negative control
group, but not as much as metformin. The best dose for decreasing blood glucose was
75 mg/kgBW. In alloxaninduced male wistar rats, ethyl acetate extract of C. cainito leaves
at 25 mg/kgBW, 50 mg/kgBW, and 75 mg/kgBW reduced blood glucose levels. The 75
mg/kgBW ethyl acetate extract of C. cainito leaves has the maximum reducing ability
compared to the 25 mg/kgBW and 50 mg/kgBW dosages. To reduce blood glucose in
alloxaninduced male wistar rats, three doses of C. cainito ethyl acetate extract were
tested (Arrijal, I. et al., 2018).

Perspective Review on Diabetes Mellitus and the Potential Anti-diabetic Activity of

Medicinal

Plants

The World Health Organization estimates that around 30 million individuals had diabetes
in 1985, and that number had risen steadily to over 171 million in 2000. The number is
expected to rise to over 366 million by 2030, mostly targeting middle-aged to elderly
people (45–64 years). For example, biguanides, thiazolidinediones, and insulin were
discovered to have anti-diabetic effects. But these medications often cause nephrological
issues, exhaustion, gastrointestinal issues (upset stomach, diarrhea, vomiting),
hypoglycemia, etc. Worldwide, many medicinal plants are used to cure diabetes. They
contain bioactive components such as flavonoids, tannins, phenolics, and alkaloids that
improve the performance of pancreatic tissues by increasing insulin secretion or
decreasing intestinal glucose absorption. Various anti-diabetic herbs have been
pharmacologically examined and proved to be useful in the treatment and prevention of
diabetes mellitus. Some research suggests that these plants can help prevent diabetic
complications and repair metabolic imbalances. There are also various putative
processes by which these herbs can control blood glucose levels. This plant (or its active
principle) can reduce plasma glucose by interfering with processes involved in glucose
homeostasis. The current study looks at the outcomes of experimental studies on the
hypoglycemic actions of plants and their bioactive components in several Asian and other
regions of the world. The kind of diabetes is briefly defined, as are the linked physiological
diseases and available anti-diabetic herbs. Finally, this analysis summarizes
hypoglycemic plant profiles found in the literature. This may help doctors, scientists, and
researchers produce evidence-based herbal remedies or dosage formulations to treat
diabetes. Extracts from many natural resources are used to create medicines to treat
hyperglycemia in diabetes mellitus. Thus, the researcher says that medicinal herbs can
be used to treat and prevent diabetes and that more research is possible (Gargantiel, M.
et al., 2021).

Effect of RRE on Different Parameters in Diabetic Rats

The hypoglycemic and hypolipidemic effects of RRE (24.11 mg/kg equivalent to 15 mg/kg
RC content), RC (15 mg/kg) and glibenclamide (600 g/kg) were studied in NA-STZ
diabetic rats for 28 days. In NA-STZ diabetic rats, hyperglycemia was confirmed by
polydipsia (thirst), hyperphagia (appetite), and weight loss. Initially, non-diabetic and
diabetic rats ate the same amount of water and food. After four weeks, diabetic rats' water
or food intake increased while their body weight decreased. Oral administration of RRE
(24.11mg/kg) and RC (15mg/kg) normalized diabetic rats' water and food intake, and
body weight without affecting normal rats (Shah, 2017). The current study used NA and
STZ to partially destroy the pancreas, resulting in higher fasting blood glucose and lower
serum insulin levels in diabetic rats. The FBG and insulin levels were normal in non-
diabetic rats given 24.11 mg/kg RRE and 15 mg/kg RC for 28 days. RRE (24.11mg/kg)
diabetic rats RC (15mg/kg) or Glb (600g/kg) gradually reduced hyperglycemia and
increased serum insulin over a 28-day period. RRE also reduced pancreatic beta cell
destruction in diabetic rats, as shown by pancreatic histopathological images. The
pancreatic protective effect of RRE is linked to its marker compound RC (Adam et.al.
2016). In hyperglycemia, excess sugar reacts with protein to form gylcated hemoglobin
(HbA1c), a laboratory marker of diabetes and associated risk of diabetic complications
(Shah, 2017). RRE (24.11mg/kg) and RC (15mg/kg) significantly reduced the increased
HbA1c level in diabetic rats compared to the standard drug Glb (600 g/kg). However,
normal treated rats' HbA1c levels were unaffected. The results match previous in vitro
studies on RRE and RC antiglycation potential (Shah, 2017).