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CURRENT SCENARIO OF TYPE II DIABETES MELLITUS

Dinesh Kawade*, Nidhi Dhote, Payal Bahadurkar, Payal Hiradewe and

Nikhil Shahu

Priyadarshini J. L. College of Pharmacy, Electronic Zone Building, MIDC, Hingna Road,

Nagpur-440016, MS, India.

ABSTRACT

Diabetes, a significant way of life issue, has become a worldwide

weight, and the pervasiveness rates are increasing steeply in creating

economies. Quick financial change with urbanization and

industrialization are the fundamental driver for the worldwide diabetes

pestilence. Among creating economies, the most noteworthy increment

in number of individuals with diabetes is in China followed by India.

In India, the plague of diabetes proceed to increment and is

encountering a move in diabetes pervasiveness from urban to rustic

regions, the well-off to the less special and from more seasoned to

more youthful individuals. Diabetes is a dynamic issue prompting

entanglements, which are extensively isolated into little vessel or

microvascular malady and huge vessel or macrovascular illness. Microvascular complexities

influence the inward piece of the eye-the retina known as diabetic retinopathy, the kidney

named as diabetic nephropathy and the fringe nerves named as diabetic neuropathy. The

macrovascular inconveniences influence the heart, the cerebrum and the fringe corridors

named as cardiovascular sickness, cerebrovascular ailment and fringe vascular ailment,

separately. India have the most extreme increment during the most recent couple of years.

Type 2 diabetes mellitus is the commonest type of diabetes.

KEYWORDS: Diabetes mellitus, disease perceptions, explanatory models, illness narratives,

type 2 diabetes.

INTRODUCTION

Type 2 diabetes is the most common type of diabetes. It is a chronic condition in which blood

glucose (sugar) can no longer be regulated. There are two reasons for this. First, the cells of

World Journal of Pharmaceutical Research SJIF Impact Factor 8.084

Volume 9, Issue 5, 329-349. Review Article ISSN 2277– 7105

Article Received on

27 February. 2020,

Revised on 17 March 2020,

Accepted on 07 April 2020

DOI: 10.20959/wjpr20205-17259

*Corresponding Author

Dinesh Kawade

Priyadarshini J. L. College

of Pharmacy, Electronic

Zone Building, MIDC,

Hingna Road, Nagpur-

440016, MS, India.

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the body become resistant to insulin (insulin resistant). Insulin works like a key to let glucose

(blood sugar) move out of the blood and into the cells where it is used as fuel for energy.

When the cells become insulin resistant, moving sugar into the cells requires more and more

insulin, and too much sugar stays in the blood. Over time, if the cells require more and more

insulin, the pancreas can't make enough insulin to keep up and begins to fail.

Epidemiology

The prevalence of diabetes is rapidly rising all over the globe at an alarming rate. Over the

past 30 yr, the status of diabetes has changed from being considered as a mild disorder of the

elderly to one of the major causes of morbidity and mortality affecting the youth and middle

aged people. It is important to note that the rise in prevalence is seen in all six inhabited

continents of the globe. Although there is an increase in the prevalence of type 1 diabetes

also, the major driver of the epidemic is the more common form of diabetes, namely type 2

diabetes, which accounts for more than 90 per cent of all diabetes cases. Nowhere is the

diabetes epidemic more pronounced than in India as the World Health Organization (WHO)

reports show that 32 million people had diabetes in the year 2000. The International Diabetes

Federation (IDF) estimates the total number of diabetic subjects to be around 40.9 million in

India and this is further set to rise to 69.9 million by the year 2025 (Fig.1).

Etiology

Type 2 diabetes is a condition in which cells cannot use blood sugar (glucose) efficiently for

energy. This happens when the cells become insensitive to insulin and the

blood sugar gradually gets too high. There are two types of diabetes mellitus, type 1 and type

2. In type 2, the pancreas still makes insulin, but the cells cannot use it very efficiently.

In type 1 diabetes, the pancreas cannot make insulin due to auto-immune destruction of the

insulin-producing beta cells.

Type 2 can be caused by

Being overweight

Eating a lot of foods or drinks with sugar and simple carbohydrates

Artificial sweeteners (sugar free sodas, sugar free foods) intake

Lack of activity (sedentary behavior)

Lack of exercise

Stress and stress hormones

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Genetics

Risk factors include

Having family members with diabetes

Being overweight

Being sedentary including watching more than 2 hours of TV per day

Drinking soda

Consuming too much sugar and processed food

Often there are no specific symptoms of the condition and it goes undiagnosed until routine

blood tests are ordered. A blood sugar level more than 125 when fasting or more than 200

randomly is a diagnosis for diabetes. Treatment is with diet and lifestyle changes that include

eating less sugary foods and fewer foods that are high in simple carbohydrates (sugar, bread,

and pasta). Sometimes a person will need to take drugs, for xample, metformin (Glucophage).

People with both types of diabetes need to monitor their blood sugar levels often to avoid

high (hyperglycemia) and low blood sugar levels (hypoglycemia). Complications include

heart and kidney disease, neuropathy, sexual and/or urinary problems, foot problems, and eye

problems.

This health condition can be prevented by following a low-glycemic load diet, staying

physically active, and getting regular medical screenings. The prognosis for a person with

this health condition is estimated to be a life expectancy of 10 years less than a person

without diabetes. However, good blood sugar control and taking steps to prevent

complications are shortening this gap, and people with the condition are living longer than

ever before. It can be reversed with diligent attention to changing lifestyle behaviors.

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Sign and Symptoms

This type of diabetes develops gradually, over years, so the signs and symptoms can seem

subtle, and you might think it is something you "just have to live with." If you are overweight

or obese, this is the major symptom, but not everyone will be overweight. In fact, weight

loss can be a symptom.

Other symptoms and signs include:

1. Fatigue

2. Frequent urination

3. Excess thirst

4. Blurry or cloudy vision

5. Wounds that won't heal

6. Tingling or numbness in the feet

7. Erectile dysfunction (ED)

8. Dark skin under the armpits and around the groin

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Signs and symptoms of low blood sugar (hypoglycemia)

Type 2 diabetes is a condition of blood sugar dysregulation. In general blood sugar is too

high, but it also can be too low. This can happen if you take your diabetes medications then

skip a meal. Blood sugar also can rise very quickly after a high glycemic index meal, and

then fall a few hours later, plummeting into hypoglycemia (low blood sugar). The signs

and symptoms of hypoglycemia can include

i Feeling dizzy or light-headed

ii Difficulty concentrating or making decisions

iii Feeling sweaty or clammy

iv Vision changes, like blurring or narrowing of the visual field

v Feeling physically weak

vi Feeling sleepy

vii Feeling irritable

Signs and symptoms of high blood sugar (hyperglycemia)

Hyperglycemia, or high blood sugar, is common in type 2 diabetes. Its signs and symptoms

can be either acute (short in duration) or chronic (last over a long period of time).

Acute symptoms include

i Feeling tired

ii Feeling vision is blurry or foggy

iii Frequent urination

iv Feeling very thirsty

Chronic signs and symptoms can include

i Darkening skin under armpits, neck, thighs

ii Fungal infections on the skin like ringworm or toenail fungus

iii Weight gain

iv Difficulty with sexual function

v Numbness, tingling, or burning sensations in the feet

Risk factors for type 2 diabetes mellitus

Risk factors for type 2 diabetes are:

Age (being over age 45)

A family history of diabetes

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Being of a race or ethnic group with a genetic predisposition for this type of diabetes

Being overweight

Having had prediabetes or gestational diabetes

Having other metabolic syndrome conditions such as high blood pressure, low HDL or

"good" cholesterol, or high triglycerides.

Pathophysiology of type 2 diabetes mellitus

Type 2 diabetes mellitus is a heterogeneous disorder with varying prevalence among different

ethnic groups. In the United States the populations most affected are native Americans,

particularly in the desert Southwest, Hispanic-Americans, and Asian-Americans. The

pathophysiology of type 2 diabetes mellitus is characterized by peripheral insulin resistance,

impaired regulation of hepatic glucose production, and declining β-cell function, eventually

leading to β -cell failure.The primary events are believed to be an initial deficit in insulin

secretion and, in many patients, relative insulin deficiency in association with peripheral

insulin resistance.

The β-cell

β-Cell dysfunction is initially characterized by an impairment in the first phase of insulin

secretion during glucose stimulation and may antedate the onset of glucose intolerance in

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type 2 diabetes .Initiation of the insulin response depends upon the transmembranous

transport of glucose and coupling of glucose to the glucose sensor. The glucose/glucose

sensor complex then induces an increase in glucokinase by stabilizing the protein and

impairing its degradation. The induction of glucokinase serves as the first step in linking

intermediary metabolism with the insulin secretory apparatus. Glucose transport inβ -cells of

type 2 diabetes patients appears to be greatly reduced, thus shifting the control point for

insulin secretion from glucokinase to the glucose transport system. This defect is improved

by the sulfonylureas. Later in the course of the disease, the second phase release of newly

synthesized insulin is impaired, an effect that can be reversed, in part at least in some

patients, by restoring strict control of glycemia. This secondary phenomenon, termed

desensitization or β-cell glucotoxicity, is the result of a paradoxical inhibitory effect of

glucose upon insulin release and may be attributable to the accumulation of glycogen within

the β-cell as a result of sustained hyperglycemia. Other candidates that have been proposed

are sorbital accumulation in the β-cell or the nonenzymatic glycation of β -cell proteins.

Other defects in β-cell function in type 2 diabetes mellitus include defective glucose

potentiation in response to nonglucose insulin secretagogues, asynchronous insulin release,

and a decreased conversion of proinsulin to insulin. An impairment in first phase insulin

secretion may serve as a marker of risk for type 2 diabetes mellitus in family members of

individuals with type 2 diabetes mellitus and may be seen in patients with prior gestational

diabetes. However, impaired first phase insulin secretion alone will not cause impaired

glucose tolerance. Autoimmune destruction of pancreatic β-cells may be a factor in a small

subset of type 2 diabetic patients and has been termed the syndrome of latent autoimmune

diabetes in adults. This group may represent as many as 10% of Scandinavian patients with

type 2 diabetes and has been identified in the recent United Kingdom study, but has not been

well characterized in other populations. Glucokinase is absent within the β-cell in some

families with maturity-onset diabetes of young. However, deficiencies of glucokinase have

not been found in other forms of type 2 diabetes. In summary, the delay in the first phase of

insulin secretion, although of some diagnostic import, does not appear to act independently in

the pathogenesis of type 2 diabetes. In some early-onset patients with type 2 diabetes

(perhaps as many as 20%), there may be a deficiency in insulin secretion that may or may not

be due to autoimmune destruction of the β-cell and is not due to a deficiency in the

glucokinase gene. In the great majority of patients with type 2 diabetes (±80%), the delay in

immediate insulin response is accompanied by a secondary hypersecretory phase of insulin

release as a result of either an inherited or acquired defect within the β-cell or a compensatory

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response to peripheral insulin resistance. Over a prolonged period of time, perhaps years,

insulin secretion gradually declines, possibly as a result of intraislet accumulation of glucose

intermediary metabolites. In view of the decline in β-cell mass, sulfonylureas appear to serve

a diminishing role in the long term management of type 2 diabetes. Unanswered is whether

amelioration of insulin resistance with earlier detection or newer insulin-sensitizing drugs

will retard the progression of β-cell failure, obviating or delaying the need for insulin therapy.

Insulin resistance

Emanating from the prismatic demonstration by Yalow and Berson of the presence of

hyperinsulinism in type 2 diabetes, insulin resistance has been considered to play an integral

role in the pathogenesis of the disease. Recent critical reviews, however, have questioned the

primacy, specificity, and contribution of insulin resistance to the disease state. As chronic

hyperinsulinemia inhibits both insulin secretion and action, and hyperglycemia can impair

both the insulin secretory response to glucose as well as cellular insulin sensitivity, the

precise relation between glucose and insulin level as a surrogate measure of insulin resistance

has been questioned. Lean type 2 diabetic patients over 65 yr of age have been found to be as

insulin sensitive as their age-matched nondiabetic controls. Moreover, in the majority of type

2 diabetic patients who are insulin resistant, obesity is almost invariably present. As obesity

or an increase in intraabdominal adipose tissue is associated with insulin resistance in the

absence of diabetes, it is believed by some that insulin resistance in type 2 diabetes is entirely

due to the coexistence of increased adiposity. Additionally, insulin resistance is found in

hypertension, hyperlipidemia, and ischemic heart disease, entities commonly found in

association with diabetes, again raising the question as to whether insulin resistance results

from different pathogenetic disease processes or is unique to the presence of type 2 diabetes.

Prospective studies have demonstrated the presence of either insulin deficiency or insulin

resistance before the onset of type 2 diabetes. Two studies have reported the presence of

insulin resistance in nondiabetic relatives of diabetic patients at a time when their glucose

tolerance was still normal. In addition, first degree relatives of patients with type 2 diabetes

have been found to have impaired insulin action upon skeletal muscle glycogen synthesis due

to both decreased stimulation of tyrosine kinase activity of the insulin receptor and reduced

glycogen synthase activity. Other studies in this high risk group have failed to demonstrate

insulin resistance, and in the same group, impaired early phase insulin release and loss of

normal oscillatory pattern of insulin release have been described. Based upon these divergent

studies, it is still impossible to dissociate insulin resistance from insulin deficiency in the

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pathogenesis of type 2 diabetes. However, both entities unequivocally contribute to the fully

established disease.

The liver

The ability of insulin to suppress hepatic glucose production both in the fasting state and

postprandially is normal in first degree relatives of type 2 diabetic patients. It is the increase

in the rate of postprandial glucose production that heralds the evolution of IGT. Eventually,

both fasting and postprandial glucose production increase as type 2 diabetes progresses.

Hepatic insulin resistance is characterized by a marked decrease in glucokinase activity and a

catalytic increased conversion of substrates to glucose despite the presence of insulin. Thus,

the liver in type 2 diabetes is programmed to both overproduce and underuse glucose. The

elevated free fatty acid levels found in type 2 diabetes may also play a role in increased

hepatic glucose production. In addition, recent evidence suggests an important role for the

kidney in glucose production via gluconeogenesis, which is unrestrained in the presence of

type 2 diabetes.

Clinical Manifestations

More thirst - When sugar builds up in your blood, your kidneys work overtime to get rid of it.

This pulls fluids from your tissues and makes you dehydrated, so you feel thirsty.

More hunger - Because diabetes can stop glucose from getting to your cells, you feel

hungry, even after you’ve eaten.

Peeing often - You’ll pee more because your kidneys are working to get rid of extra sugar in

your system.

Dry mouth - Dehydration and peeing a lot can drain moisture from your mouth as well.

Weight loss without trying - When you lose sugar from peeing a lot, you lose calories, too.

You might lose weight even though you’re eating as usual.

Fatigue - When your body can’t use energy from food, you could feel weak

and tired. Dehydration can make you feel this way, too.

Blurry vision - High blood sugar can make you have trouble focusing.

Headaches - High blood sugar levels can cause your head to hurt.

Loss of consciousness - After you exercise, skip a meal, or take too much medication, your

blood sugar could go too low, and you could pass out.

Infections or sores that don’t heal - High blood sugar can slow blood flow and make it

harder for your body to heal.

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Tingling hands and feet - Type 2 diabetes can affect nerves in your hands and feet.

Red, swollen, tender gums - You might be more likely to get infections in your gums and the

bones that hold your teeth in place. Your gums may get infected or pull away from your teeth.

Your teeth might become loose.

Complications of Type 2 Diabetes

It’s important to get your blood sugar under control to avoid these serious conditions:

Hypoglycemia - If your blood sugar falls below 70 milligrams per deciliter (mg/dL), it can

lead to accidents, coma, and death.

Hyperglycemia - Blood sugar that goes above 180 to 200 mg/dL can give you heart, nerve,

kidney, and vision problems. Over the long term, it also can cause coma and death.

Over time, people with type 2 diabetes may have other health problems:

Diabetic ketoacidosis - When you don’t have enough insulin in your system, your blood

sugar rises, and your body breaks down fat for energy. Toxic acids called ketones build up and

spill into your urine. It can cause coma and death if you don’t treat it.

Heart and blood vessel diseases - People with diabetes are more likely to have conditions

like high blood pressure and high cholesterol, which play a role in heart disease. Also, high

blood sugar can damage your blood vessels and the nerves that control your heart.

High blood pressure - Diabetes doubles your risk of high blood pressure, which makes you

more likely to have heart disease or stroke.

Nerve damage (diabetic neuropathy) - This can cause tingling and numbness, most often in

your feet and legs. But it can also affect your digestive system, urinary tract, blood vessels, and

heart.

Eye damage - Diabetes can cause:

Glaucoma, a buildup of pressure in your eyes

Cataracts, a cloudiness of your lens

Retinopathy, which is damage to the blood vessels in your eyes

Kidney disease -Your kidneys may have to work harder to filter out the extra sugar, along

with all the other waste products in your blood.

Hearing problems - Doctors aren’t sure why this happens, but they think high blood sugar

levels damage the small blood vessels in your ears.

Skin problems - Diabetes can cause:

Infections - You’re more likely to get bacterial and fungal infections.

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Itching - Causes include infections, dry skin, and poor circulation. You might notice it on your

lower legs.

Acanthosis nigricans - These velvety darker areas can appear on your neck, armpits, groin,

hands, elbows, and knees.

Diabetic dermopathy - Changes to small blood vessels that look like red or brown scaly

patches. They often show up on your feet and the fronts of your legs.

Necrobiosis lipoidica diabeticorum - This rare condition also affects your blood vessels. It

starts as a dull, red, raised area, but winds up as a shiny scar with a violet border. Your skin

could itch or crack open. Women are more likely to get this than men.

Allergic reactions - You could get these in response to insulin or another diabetes medication.

Diabetic blisters(bullosis diabeticorum) - These sores look like burn blisters and can show

up on the backs of your fingers, hands, toes, feet, and sometimes legs or forearms.

Disseminated granuloma annulare - You might get red, brown, or skin-colored rings or arc-

shaped raised areas on your fingers, ears, or trunk.

Type 2 Diabetes in Children

Type 2 was once called adult-onset diabetes because it was rare in children and teens. But it has

become more common since the mid-1990s, in large part because more young people are

overweight or obese, a risk factor for the disease.

Children are also at higher risk of type 2 diabetes if they don’t get enough exercise or if they have

a close relative with the condition. African American, Hispanic, Native American, Alaska Native,

Asian American, and Pacific Islander children are more likely to get it.

Type 2 Diabetes in Older Adults

Your risk of type 2 diabetes goes up as you age because your body can become resistant to

insulin and your pancreas might not work as well as it used to.

Diabetes is more likely to cause complications in people 65 and older, especially heart

attacks, eye problems, loss of a leg (amputation), and kidney disease.

Screening

Persons older than 40 years of age should be screened annually. More frequent screening is

recommended for individuals with additional risk factors for diabetes.

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Certain races/ethnicities (Native American, African American, Hispanics or Asian

American, Pacific Islander),

Overweight or obese persons with a BMI greater than or equal to 25 kg/m2 or 23 kg/m2

in Asian Americans,

First-degree relative with diabetes mellitus

History of cardiovascular disease, hypertension

Low HDL-cholesterol or hypertriglyceridemia,

Women with polycystic ovarian syndrome

Physical inactivity

Conditions associated with insulin resistance, for example, Acanthosis nigricans.

Women diagnosed with gestational diabetes mellitus (GDM) should have lifelong testing at

least every three years. For all other patients, testing should begin at age 45 years, and if

results are normal, patients should be tested at a minimum of every 3-years.

The same tests are used to both screen for and diagnose diabetes. These tests also detect

individuals with prediabetes.

Diagnosis

Diabetes can be diagnosed either by the hemoglobin A1C criteria or plasma glucose

concentration (fasting or 2-hour plasma glucose).

Fasting Plasma Glucose (FPG)

A blood sample is taken after an 8 hour overnight fast. As per ADA, fasting plasma glucose

(FPG) level of more than 126 mg/dL (7.0 mm/L) is consistent with the diagnosis.

Two-Hour Oral Glucose Tolerance Test (OGTT)

In this test, the plasma glucose level is measured before and 2 hours after the ingestion of 75

gm of glucose. DM is diagnosed if the plasma glucose (PG) level in the 2-hour sample is

more than 200 mg/dL (11.1mmol/L). It is also a standard test but is inconvenient and more

costly than FPG and has major variability issues. Patients need to consume a diet with at least

150 g per day of carbohydrate for 3 to 5 days and not take any medications that can impact

glucose tolerance, such as steroids and thiazide diuretics.

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Glycated Hemoglobin (Hb) A1C

This test gives an average of blood glucose over the last 2 to 3 months. Patients with an Hb

A1C greater than 6.5% (48mmol/mol) are diagnosed as having DM. Hb A1C is a convenient,

rapid, standardized test and shows less variation due to pre-analytical variables. It is not much

affected by acute illness or stress.

Hb A1C is costly and has many issues, as discussed below, including lower sensitivity. Hb

A1C should be measured using the National Glycohemoglobin Standardization Program

(NGSP) certified method standardized to Diabetes Control and Complications Trial (DCCT)

assay. It is affected by numerous conditions such as sickle cell disease, pregnancy,

hemodialysis, blood loss or transfusion, or erythropoietin therapy. It has not been well

validated in non-Caucasian populations.

Anemia due to deficiency of iron or vitamin B12 leads to spurious elevation of Hb A1C,

limiting its use in countries with a high prevalence of anemia. Also, in children and the

elderly, the relation between Hb A1C and FPG is suboptimal.

For all of the above tests, if the person is asymptomatic, testing should be repeated later to

make a diagnosis of diabetes mellitus.

In patients with classic symptoms of hyperglycemia (increased thirst, increased hunger,

increased urination), random plasma glucose more than 200 mg/dL is also sufficient to

diagnose DM.

FPG, 2-hour PG during 75-g GTT, and Hb A1C are equally appropriate for the diagnosis of

DM. There is no concordance between the results of these tests.

Differential Diagnosis

The list of differential diagnosis of diabetes mellitus consists of various conditions that would

exhibit similar signs and symptoms:

Drug-induced signs and symptoms due to corticosteroids, neuroleptics, pentamidine, etc

Genetic aberrations in beta-cell function and insulin action

Metabolic syndrome (syndrome X)

Infection

Endocrinopathies such as acromegaly, Cushing disease, pheochromocytoma,

hypothyroidism, etc

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Complications of iron overload (hemochromatosis)

Conditions affecting the exocrine part of the pancreas such as pancreatitis, cystic fibrosis,

etc.

Prognosis

DM is associated with increased ASCVD, and treating BP, statin use, regular exercise, and

smoking cessation are of great importance in ameliorating risk. The overall excess mortality

in those with T2DM is around 15% higher but varies widely. The prevalence of vision-

threatening diabetic retinopathy in the United States is about 4.4% among adults with

diabetes, while it is 1% for end-stage renal disease. Today, with pharmacotherapy for

hyperglycemia, as well as lowering LDL cholesterol and managing BP with ACE/ARB

therapy, with other antihypertensive medications and aspirin in secondary prevention,

vascular complications can be managed adequately resulting in a reduction in morbidity and

mortality.

Treatment of T2DM

Non-pharmacologic Treatment

It is well-established that lifestyle plays a crucial role in prevention and treatment of T2DM.

The ADA endorses the education of diabetes self-management. This education can help the

patient to obtain necessary knowledge and skills for self-care, manage hyperglycemia and

possible hypoglycemia, and make lifestyle changes. Primary non-pharmacological

interventions mainly include appropriate nutritional diet, regular physical exercise and

smoking cessation. Diet and regular exercise from moderate to intense can improve glucose

levels in patients with T2DM and those at risk for developing obese and T2DM. Lifestyle

intervention is a proven strategy for reducing diabetes incidence. Nevertheless, the

intervention is considered effective only in the short term but is difficult to adhere to in the

long run, thus limiting its effectiveness.

Anti-diabetes pharmacotherapy

The ultimate goal for the pharmacotherapy is to modify disease progression in a manner

preventing pathophysiological decline towards β-cell dysfunction and long-term

complications associated with hyperglycemia. People should be aware that all anti-diabetic

drugs except insulin require some degree of residual pancreatic β-cells to perform function. A

single anti-hyperglycemic drug often suffices initially, but a second drug with a different

mechanism of action usually is required with the disease progression. In advanced T2DM,

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insulin intervention may be necessary. For convenience, oral agents are typically the first

choice for the treatment of T2DM but oral delivery bears some drawbacks such as frequent

dosing, short half life, and low bioavailability. We outline major anti-diabetic drugs for their

efficacy, safety and mechanisms of action in the following pages. It is important for both

clinicians and patients to obtain a broad understanding of each class of oral agents so as to

optimize diabetic control. In addition, despite the availability of many oral anti-diabetic

agents, therapeutic efficacy in some of them is offset by side effects such as weight gain and

hypoglycemia. Furthermore, treatment with glucose-lowering agents is generally

characterized by loss of efficiency over time, due to progressive β-cell dysfunction. Thereby,

there is an unceasing requirement for adjustment including agent dose, and/or agent type or a

combination of different agents in all stages of the disease.

Metformin: Metformin is one of the oldest but the safest agents used in the treatment of

T2DM. Metformin is the first choice of recommended therapy for T2DM according to the

International Diabetes Federation Global Guideline for T2DM, in agreement with similar

guidelines from the ADA, as well as the European Association for the Study of Diabetes

(EASD). Metformin exerts its effects primarily by reducing hepatic glucose output through

inhibition of gluconeogenesis and has a comparatively lesser effect increasing insulin

sensitivity. Hence, unlike insulin or sulfonylureas, metformin is primarily an

antihyperglycemic agent, rather than a hypoglycemic agent. As a result, metformin does not

cause hypoglycemia. In addition, it does not cause weight gain due to its anorexic effect.

Weight gain can worsen the course of the disease in the long run [. Metformin also modestly

reduces plasma triglyceride concentrations resulting from decreased production of very low

density lipoprotein and has favorable effects on a number of cardiovascular risk factors such

as lipids, body weight, blood pressure and platelet function. Therefore, metaformin is

particularly suitable for T2DM obese patients with cardiovascular diseases. Another

advantage of metformin is the reduction of mortality, as documented in the UKPDS. The

most common reported adverse reaction to metformin therapy is gastrointestinal upset

including nausea, vomiting, anorexia and diarrhea. Thus, metformin should be started at a

low dose at first (500 mg PO bid).

Sulfonylureas: Sulfonylurea binds to the sulfonylurea receptor on the surface of the β-cells

and inhibits potassium efflux, thus depolarizing the β-cells and facilitating insulin release.

Because sulfonylurea acts by stimulating insulin release from β-cells, patients without a

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sufficient number of β-cells, such as those with later stages of T2DM, do not respond to the

medication. An advantage of sulfonylureas is its low cost to patients. Its disadvantage is that

sulfonylurea treatment carries a risk of hypoglycemia, especially in elderly patients. In

addition, the drug promotes weight gain. Many patients can increase more than 2 kg after

initiative medication. Furthermore, sulfonylureas are associated with a higher cardiovascular

risk than metformin likely due to impairment of endothelial function with increased risk for

ischemic complications.

GLP1 receptor agonists and DPP-4 inhibitors: Glucagon-like peptide 1 (GLP-1) is a 30-

amino-acid peptide. It is an incretin hormone produced by ileum and colon, and released into

the bloodstream. GLP-1 is released in response to meal ingestion and blood glucose

concentration in a harmonized fashion for hormone release. GLP-1 also exerts an anti-

diabetic effect by delaying gastric emptying, suppressing glucagon release and increasing

glucose-stimulated insulin release. The resulting effect of GLP-1 is to curb postprandial

hyperglycemia, but its half-life after secretion into the blood is very short. Thus, two

strategies are used to overcome this problem.

A) Incretin mimetic such as liraglutide, approved by FDA in 2010, is a long acting GLP-1

degradation enzyme analogue for treatment of T2DM. It has a long half-life of 14 h and is

resistant to dipeptidyl peptidase-4 (DPP-4) degradation.

B). GLP-1 degradation enzyme inhibitors like DPP-4 is the newest class of oral agents for the

treatment of T2DM. DPP-4 inhibitors such as vildagliptin, sitagliptin, saxagliptin, linagliptin

and alogliptin inhibit the enzymatic degradation of GLP-1. As a consequence, GLP-1

concentration increases, leading to decreased postprandial glucose level. DPP-4 inhibitors

and incretin mimetics do not carry a risk of hypoglycemia, as these drugs seldom alter insulin

secretion levels during fasting state. Another major advantage of the DPP-4 inhibitors is to

retain body weight when the patient is mal-nourished or under weight. DPP-4 inhibitors are

approved for both monotherapy and co-deliver with metformin and thiazolidinediones. DPP-

4 inhibitors have gastrointestinal side effects and may cause urticaria. Moreover, cost of

DPP-4 inhibitors is high, a major limiting factor for their clinical use.

Thiazolidinediones: Thiazolidinediones (TZDs) including rosiglitazone and pioglitazone are

drugs acting as insulin sensitizers. The effects of TZDs are mediated through peroxisome

proliferatoractivated receptor-γ (PPAR-γ). PPAR- receptors are mainly located in the

adipocytes, and also distributed in skeletal muscle, liver and the pancreatic β-cells. The TZD-

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PPAR complex acts on response elements in promoter regions to affect the transcription of

many genes. They may stimulate production of proteins that increase insulin sensitivity and

block transcription of proteins responsible for insulin resistance or inflammation. In addition

to glucose-lowering effects, pioglitazone may also improve lipid profiles, possibly due to its

partial PPAR-α activity. Pioglitazone has a very low risk of hypoglycemia in monotherapy.

SGLT-2 inhibitors: Sodium-glucose co-transporter 2 (SGLT2) inhibitors are another new

class of anti-diabetic drug with an insulinindependent mechanism. The SGLT2 is a

transporter found in the kidney proximal tubule and is responsible for approximately 90% of

renal glucose reabsorption. The SGLT2 inhibitors like dapagliflozin are highly selective

SLGT2-inhibitors and reduce reabsorption of glucose in the kidney. As a consequence,

glucose excretion increases in the urine, resulting in glycouria, whereas plasma glucose levels

decrease in blood, an insulin independent reduction. Thus, SGLT-2 inhibitors do not confer

any risk of hypoglycemia. In addition to improvements in glycemic control, dapagliflozin

therapy is also associated with a beneficial reduction in total body weight. A disadvantage for

SGLT-2 inhibitors is an increased incidence of genital infections.

Alpha-glucosidase inhibitors (AGIs): AGIs such as acarbose, voglibose and miglitol are

pseudo-carbohydrates that competitively inhibit α-glucosidase enzymes located in the brush

border of small intestine that hydrolyze non-absorbable polysaccharides and oligosaccharides

into absorbable monosaccharides. As a result, the effect of these drugs is to retard glucose

absorption after a meal, and consequently lowers postprandial insulin levels and

hyperglycemia peaks in patients with few β-cell reserves. AGIs are commonly used to control

postprandial blood glucose and to reduce the insulin requirement without causing

hypoglycemia and weight gain. AGIs can be administered as monotherapy or in combination

with any other blood glucose-lowering drug, including insulin for the treatment of T2DM.

The primary drawback of α-glucosidase inhibitors is its gastrointestinal disturbance such as

flatulence and diarrhea.

Strategies for insulin therapy: Insulin therapy was classically considered a last step for

T2DM patients and did not use until all other treatments failed. The goals of insulin therapy

in T2DM are glycemic and metabolic control to prevent micro- and macrovascular

complications. People should be aware if the insulin dose is too high or incorrectly

distributed, hypoglycemia and marked weight gain may occur. The treatment begins at a dose

of 10 to 20 IU of a long-acting insulin preparation. Depending on the patient’s weight, a dose

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increase by 2 IU every three days may be required until the morning glucose values are

within the target range. If glycemic peaks after meals are the main problem, then insulin

therapy would more reasonably be initiated with insulin administration only at mealtimes. It

is increasingly being recognized that insulin may be used at an early stage of T2DM. Recent

treatment guidelines recommend the use of insulin, especially basal insulin, as part of an

early treatment regimen in the disease process. The early insulin therapy may slow or even

halt diabetes progression. In patients with newly diagnosed T2DM, several small-scale

studies have demonstrated that short term intensive insulin treatment can induce disease

remission (defined by normal glucose levels) for up to 2 years. The ADA and EASD

recommend starting insulin treatment with basal insulin based on both the efficacy and

relative safety of this approach. Currently available basal insulin analogs, such as insulin

glargine (Lantus; Sanofi, Paris, France) and insulin detemir (Levemir; Novo Nordisk Inc,

Plainsboro, NJ) offer better improvement in terms of duration of action and reduced peak

effect.

Bariatric surgery: Bariatric surgery includes Roux-en-Y gastric bypass (RYGB),

laparoscopic sleeve gastrectomy (LSG), laparoscopic adjustable gastric banding (LAGB),

biliopancreatic diversion (BPD) and the biliopancreatic diversion with a duodenal switch

(BPD-DS). The RYGB and the BPD procedures bypass a full length of normal intestine

(bypass procedures) whereas the LAGB and LSG only restrict the normal flow of food

(restrictive procedures). Most T2DM patients are overweight or obese. Patients with T2DM

and body mass index (BMI) 35 kg/m2 are currently eligible for bariatric surgery, according to

the NIH Consensus Criteria for bariatric surgery. Recent meta-analyses of 16 studies with

6131 patients and mean 17.3-month follow-up have found bariatric surgery to be superior to

conventional medical therapy in achieving significant weight loss, HbA1c and fasting plasma

glucose reduction and diabetes remission. Thus, bariatric surgery has been accepted as the

most effective treatment along with significant metabolic benefits for patients with T2DM

and BMI >35 kg/ m2. Weight loss after surgery is not due to intestinal malabsorption, but due

to decreased food consumption from decreased appetite. Evidence exists that changes in the

gut hormonal milieu after gastric bypass can improve insulin resistance immediately after

surgery and proceed substantial weight loss.

Chinese herbal medicines: As mentioned above, a number of anti-diabetic drugs are

effective for T2DM treatment. However, these medications frequently have side effects, such

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as weight gain, bone loss, and increased risk of cardiovascular events. These side effects

could become more prevalent due to continuous treatment of chronic diseases. Herbal

medications can be a good alternative in combination with or as a partial replacement for

Western medications. Because herbal medicines are usually derived from natural plants, they

are considered to be relatively safe and have fewer side effects compared to the conventional

drugs. Herbal medicine has long been used in China in the treatment of diabetes for several

thousands of years and currently it has been intensively used for diabetes treatment. Over

70% of Chinese patients are treated with traditional Chinese herbal medicines. Diabetes is a

huge burden in China, where approximately 100 million people have been diagnosed with the

disease and the prevalence is 9.7% in China. The application of herbal medicines for diabetic

patients is increasing in clinics across the United States. Investigation shows that among

people with diabetes, 22.3% of patients use herbal therapy or folk medicine. It is estimated

that more than 200 species of plants exhibit hypoglycaemic properties. The investigation

shows that about 33 Chinese traditional medicines such as Radix Astragali seu Hedysari,

Radix Rehmanniae and Radix Rehmanniae, Praeparata, Radix Trichosanthis, are most

frequently used in Chinese traditional prescriptions for the clinical treatment of diabetes and

its complications. Some Chinese anti-diabetic herbs have been proven effective although

some research findings are not consistent. Clinical evidence and animal tests show that many

Chinese herbs are beneficial in lowering blood glucose and increase insulin sensitivity.

Mechanism and philosophy of Chinese herbal medicines and Western medicine are different.

CONCLUSION

The past decades have witnessed a rapid rise in the prevalence of diabetes, especially in the

urban areas. The fact that there is a shift in age of onset to younger age groups is alarming as

this could have adverse effects on the nation’s economy. Hence, the early identification of at

risk individuals and appropriate intervention in the form of weight reduction, changes in

dietary habits and increased physical activity could greatly help to prevent, or at least delay,

the onset of diabetes and thus reduce the burden due to non communicable diseases in India.

We describe the current understanding of T2DM diagnostic criteria and antidiabetic

medications including Chinese herbs. We highlight some issues that should be addressed for

clinicians and patients. Although T2DM diagnosis and treatment have been improved in the

past decade, current available medicines are not able to completely curb the development of

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T2DM and its complications. Thus, it is important to develop new drugs with improved

safety and efficacy for treatment of T2DM in the future.

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