**4. Management of diabetes mellitus**

61]; and diffusion of AGE precursors out of the cell and their modification of circulating proteins in the blood, such as albumin, which can then bind to AGE receptors and activate them thereby causing the production of inflammatory cytokines and growth factors, which in

PKCs are a family of at least 11 isoforms that are widely distributed in mammalian tissues. The enzyme phosphorylates various target proteins. The activity of the classic isoforms is depend‐ ent on both Ca2+ ions and phosphatidylserine and is greatly enhanced by diacylglycerol (DAG) [53]. Intracellular hyperglycaemia increases the *de novo* synthesis of DAG from the glycolytic intermediatedihydroxyacetonephosphatebyreducingittoglycerol-3-phosphate andstepwise acylation[66].HyperglycaemiamayalsoactivatePKCisoforms indirectlythroughbothligation of AGE receptors[67] and increased activity of the polyol pathway [68], presumably by increasingreactiveoxygenspecies.OnesignificanteffectofPKCactivationisseeninthedecrease in the vasodilator producing endothelial nitric oxide (NO) synthase (eNOS), while the vasocon‐ strictor endothelin-1 is increased. Transforming growth factor- β and plasminogen activator inhibitor-1 are also increased [69].Abnormal activation of PKC has been implicated in the decreased glomerular production of nitric oxide induced by experimental diabetes [70], and in the decreased production of nitric oxide in smooth muscle cells that is induced by hyperglycae‐ mia [71]. Activation of PKC also contributes to increased microvascular matrix protein accumulation by inducing expression of TGF-b1, fibronectin and type IV collagen both in

Glucose is one of the most largely used energy substrate in living cells. A fraction (2–3%) of the glucose entering the cell is converted into UDP–N-Acetyl Glucosamine (UDP-GlcNAc), through the hexosamine biosynthetic pathway (HBP). The level of UDPGlcNAc in the cell thus reflects the flux of glucose through this pathway [73]. In this pathway, fructose-6-phosphate is diverted from glycolysis to provide substrates for reactions that require UDP-*N* acetylglu‐ cosamine, such as proteoglycan synthesis and the formation of *O*-linked glycoproteins [23]. O-GlcNAcylation may affect the phosphorylation status of a protein, by regulating the phosphorylation of adjacent residues or by competing for the same serine or threonine residue (the so-called Yin-Yang mechanism), in which modification of a serine or threonine residue by either phosphorylation or O-GlcNAcylation differently affects the protein's function [73]. O-GlcNAcylations also regulate insulin signaling and seem to play an important part in the development of diabetes and its complications [74,75]. Inhibition of the rate-limiting enzyme in the conversion of glucose to glucosamine, glutamine:fructose-6-phosphate amidotransfer‐ ase (GFAT), blocks hyperglycaemia-induced increases in the transcription of TGF-α, TGF-β1. This pathway has been shown to play a role both in hyperglycaemia-induced abnormalities of glomerular cell gene expression and in hyperglycemia-induced cardiomyocyte dysfunction

turn cause vascular pathology [62-65].

144 Antioxidant-Antidiabetic Agents and Human Health

**3.3. Activation of protein kinase C (PKC)**

cultured mesangial cells [72] and in glomeruli of diabetic rats [66].

**3.4. Increased flux through the hexosamine pathway**

in cell culture [25,76].

Diabetes mellitus is a syndrome implying that efforts targeted at its management should be multifaceted. Adequate consideration should be given to all the accompanying comorbidities and all symptomatic and asymptomatic features. Efforts should be geared towards the attainment of normal or near normal glucose levels. The general objective of diabetes man‐ agement include to (i) relieve symptoms (ii) correct associated health problems and reduce morbidity, mortality and economic costs of diabetes (iii) prevent as much as possible acute and long-term complications (iv) monitor the development of such complications and provide timely intervention and, (v) improve the quality of life and productivity of the individual with diabetes [77]. The orthodox approach to the management of diabetes mellitus has always included lifestyle modification and dietary therapy, administration of oral antidiabetic drugs, and insulin therapy.

#### **4.1. Diet and lifestyle modification**

Weight reduction and an increase in daily energy expenditure decrease insulin resistance and increase glucose tolerance [78]. Advice on diet and exercise are an important part of the treatment of T2DM and overweight patients are normally advised to restrict calorie intake, consume food with low total (especially saturated) fat content and high (predominately unrefined) carbohydrate content.

Dietary and lifestyle modifications are regarded as the mainstay of treatment and management for T2DM. The majority of people with T2DM are overweight and usually have other metabolic disorders of the insulin resistance syndrome. Therefore, the major aims of dietary and lifestyle changes are to reduce weight, improve glycaemic control and reduce the risk of coronary heart disease (CHD), which accounts for 70- 80% of deaths among those with diabetes [79]. Even modest weight reduction is associated with a reduction in insulin resistance, a reduction in hepatic glucose production, and perhaps, an improved islet β-cell function [80,81]. Several studies have demonstrated the effectiveness of diet and exercise in reducing the progression of diabetes [82-85].

Fat is the most energy-rich of all nutrients and reduction of fat intake helps to reduce total energy intake, which is important for many people with type 2 diabetes and some with type 1 diabetes. Results from several research studies suggest that populations consuming a low saturated fat diet have lower incidence and mortality from CHD compared with those living in countries with a high intake of saturated fat and that reduced saturated fat intake is associated with reduced levels of low-density lipoprotein (LDL) – cholesterol [86,87].

#### **4.2. Oral antidiabetic drugs**

Oral antidiabetic drugs (OADs) are normally introduced when lifestyle modifications fail to adequately control glycaemia. They are very useful for managing hyperglycaemia, especially in the early stages of disease. However, there are several limitations that prevent OADs from reaching their potentials [88]. Sulfonylureas cause hypoglycaemia by stimulating insulin release from pancreatic β -cells. They bind to sulfonylurea (SUR) receptors on the β -cell plasma membrane, causing closure of adenosine triphosphate (ATP)-sensitive potassium channels, leading to depolarization of the cell membrane. This in turn opens voltage-gated channels, allowing influx of calcium ions and subsequent secretion of preformed insulin granules [89]. Acute administration of sulfonylureas T2DM patients increases insulin release from the pancreas and also may further increase insulin levels by reducing hepatic clearance of the hormone. Initial studies showed that a functional pancreas was necessary for the hypoglycae‐ mic actions of sulfonylureas [90]. With chronic administration, circulating insulin levels decline to those that existed before treatment. But, despite this reduction in insulin levels, reduced plasma glucose levels are maintained [89].

the hyperglycaemic state. In lean patients with T2DM, impaired insulin secretion is a common defect, and insulin resistance tends to be less severe than in obese patients with T2DM [100].

Antidiabetic Botanicals and their Potential Benefits in the Management of Diabetes Mellitus

http://dx.doi.org/10.5772/57339

147

**5. Limitations of orthodox approaches in the treatment of diabetes mellitus**

Despite the significant improvements recorded from the administration of the currently available therapies in the treatment of diabetes, several undesirable side effects have been observed in the course of treatment using these therapies. Reports have shown that the success of OADs is limited by their mechanisms of action, which often address the symptoms of diabetes rather than its underlying pathophysiology. For instance, up to 2.5% and 17.5% of sulfonylurea (SU)-treated patients experience major and minor hypoglycaemia, respectively, while gastrointestinal (GI) problems affect up to 63% of metformin, and 30% of acarbosetreated patients. These side effects can have a negative impact on patient adherence to treatment, resulting in higher HbA1c levels and increased risk for all-cause hospitalization and

Another limitation that hinders the efficacy of OADs is the tendency of health professionals to delay initiation and intensification of therapy. OADs are frequently initiated too late in the progression of the disease and intensification is delayed and thus exposes the patient to hyperglycemia [88]. According to the recent American Association of Clinical Endocrinologists (AACE) road map guidelines, combination therapy is to be initiated when continous titration

Although insulin is the most effective antihyperglycemic agent, its initiation is also delayed to an excessive degree. Brown *et al.* estimated that the average patient accumulated HbA1c- which contribute to excess glyacemic burden (HbA1c > 8%) from diagnosis until insulin initiation, thereby increasing the prevalence of complications [103]. The economic burden of managing diabetes is also a limitation to the use of oral antidiabetic drugs especially in less developed countries where the people can scarcely afford orthodox treatment. There is therefore the need to investigate the antidiabetic effects of indigenous plants and their continuous role in the management of diabetes mellitus with a view to developing new and more effective drugs to

Terrestrial plants have been used as medicines in Egypt, China, India and Greece from ancient time and an impressive number of modern drugs have been developed from them [104]. According to the World Health Organization (WHO), a medicinal plant is any plant which, in one or more of its organs contains substances that can be used for therapeutic purposes, or which are precursors for chemo-pharmaceutical semi synthesis. Such a plant will have its parts including leaves, roots, rhizomes, stems, barks, flowers, fruits, grains or seeds, employed in the control or treatment of a disease condition and therefore contains chemical components

of OAD monotherapy fails to achieve target HbA1c levels (ie, ≤ 6.5%) [102].

**6. Therapeutic and chemoprophylactic potentials of botanicals**

stem the tide of the ravaging epidemic of diabetes.

all-cause mortality [101].

Metformin, the popular antidiabetic drug has its origin in the plant *Galega officinalis.* It is one of the major success stories of the reward of prospecting for drugs from botanical sources. Metformin is antihyperglycaemic, not hypoglycaemic [91]. Clarke *et al.*reported that metfor‐ min does not cause insulin release from the pancreas and does not cause hypoglycaemia, even in large doses [92]. Metformin has been shown to increase peripheral uptake of glucose and to reduce hepatic glucose output by approximately 20-30% when given orally but not intra‐ venously [93,94]. Impaired absorption of glucose from the gut has also been suggested as a mechanism of action, but has not been shown to have clinical relevance. Metformin has also been shown to decrease serum triglycerides and fatty acid concentrations and slows the rate of lipid oxidation. These actions indirectly inhibit gluconeogenesis [95].

The meglitinide analogues act on β-cell receptors to stimulate insulin secretion by binding to the sulfonylurea receptor subunit and closing the K+ ATP channel but probably at a site distinct from that of the sulfonylurea receptor [96,97]. Closure of the potassium channel leads to depolarization of β-cell plasma membrane, which promotes influx of calcium ions through voltage-gated calcium channels, resulting in exocytosis of insulin granules [89]. α-Glucosidase inhibitors competitively block small intestine brush border enzymes that are necessary to hydrolyze oligo and polysaccharides to monosaccharides [98]. Inhibition of this enzyme slows the absorption of carbohydrates and the postprandial rise in plasma glucose is blunted in both normal and diabetic subjects [99].

#### **4.3. Insulin**

Insulin has proven to be the therapy with the highest potential to achieve glycaemic target in diabetics. It is typically prescribed after OADs have failed, and often later than is ideal [88]. The physiological plasma insulin profile in healthy individuals displays low but constant insulin levels in fasting conditions, with sharp prandial peaks shortly (within 30 minutes) after meals followed by a slow return to basal levels when increased insulin secretion is no longer necessary. In order to avoid glycaemic excursions, exogenously administered insulin would ideally closely mimic the healthy physiological pharmacokinetic insulin profile [88].

Although all patients with T2DM become relatively insulinopenic late in the course of their disease, some patients with T2DM may have insufficient insulin secretion early in the course of the disease. This difference arises from the heterogeneity in the metabolic expression of the diabetic state and the difference in the extent to which different abnormalities contribute to the hyperglycaemic state. In lean patients with T2DM, impaired insulin secretion is a common defect, and insulin resistance tends to be less severe than in obese patients with T2DM [100].

release from pancreatic β -cells. They bind to sulfonylurea (SUR) receptors on the β -cell plasma membrane, causing closure of adenosine triphosphate (ATP)-sensitive potassium channels, leading to depolarization of the cell membrane. This in turn opens voltage-gated channels, allowing influx of calcium ions and subsequent secretion of preformed insulin granules [89]. Acute administration of sulfonylureas T2DM patients increases insulin release from the pancreas and also may further increase insulin levels by reducing hepatic clearance of the hormone. Initial studies showed that a functional pancreas was necessary for the hypoglycae‐ mic actions of sulfonylureas [90]. With chronic administration, circulating insulin levels decline to those that existed before treatment. But, despite this reduction in insulin levels,

Metformin, the popular antidiabetic drug has its origin in the plant *Galega officinalis.* It is one of the major success stories of the reward of prospecting for drugs from botanical sources. Metformin is antihyperglycaemic, not hypoglycaemic [91]. Clarke *et al.*reported that metfor‐ min does not cause insulin release from the pancreas and does not cause hypoglycaemia, even in large doses [92]. Metformin has been shown to increase peripheral uptake of glucose and to reduce hepatic glucose output by approximately 20-30% when given orally but not intra‐ venously [93,94]. Impaired absorption of glucose from the gut has also been suggested as a mechanism of action, but has not been shown to have clinical relevance. Metformin has also been shown to decrease serum triglycerides and fatty acid concentrations and slows the rate

The meglitinide analogues act on β-cell receptors to stimulate insulin secretion by binding to

from that of the sulfonylurea receptor [96,97]. Closure of the potassium channel leads to depolarization of β-cell plasma membrane, which promotes influx of calcium ions through voltage-gated calcium channels, resulting in exocytosis of insulin granules [89]. α-Glucosidase inhibitors competitively block small intestine brush border enzymes that are necessary to hydrolyze oligo and polysaccharides to monosaccharides [98]. Inhibition of this enzyme slows the absorption of carbohydrates and the postprandial rise in plasma glucose is blunted in both

Insulin has proven to be the therapy with the highest potential to achieve glycaemic target in diabetics. It is typically prescribed after OADs have failed, and often later than is ideal [88]. The physiological plasma insulin profile in healthy individuals displays low but constant insulin levels in fasting conditions, with sharp prandial peaks shortly (within 30 minutes) after meals followed by a slow return to basal levels when increased insulin secretion is no longer necessary. In order to avoid glycaemic excursions, exogenously administered insulin would

Although all patients with T2DM become relatively insulinopenic late in the course of their disease, some patients with T2DM may have insufficient insulin secretion early in the course of the disease. This difference arises from the heterogeneity in the metabolic expression of the diabetic state and the difference in the extent to which different abnormalities contribute to

ideally closely mimic the healthy physiological pharmacokinetic insulin profile [88].

ATP channel but probably at a site distinct

of lipid oxidation. These actions indirectly inhibit gluconeogenesis [95].

reduced plasma glucose levels are maintained [89].

146 Antioxidant-Antidiabetic Agents and Human Health

the sulfonylurea receptor subunit and closing the K+

normal and diabetic subjects [99].

**4.3. Insulin**
