1. Type 2 Diabetes Mellitus (T2DM)
Definition of Diabetes Millitus:
Diabetes mellitus is a metabolic syndrome of multiple etiologies characterized by chronic hyperglycemia
with disturbances of carbohydrate, fat and protein metabolism. Diabetes occurs either when the
pancreas does not produce enough insulin or when the body cannot effectively use the insulin it
produces. This disorder is often associated with long term complications involving organs like eyes,
kidneys, nerves, heart and blood vessels.
Epidemiology & Key facts:
Worldwide, the number of people with diabetes rose from 108 million in 1980 to 422 million in 2014 &
prevalence has been rising more rapidly in low- and middle-income countries than in high-income
countries. Diabetes is a major cause of blindness, kidney failure, heart attacks, stroke and lower limb
amputation. In 2014, 8.5% of adults aged 18 years and older had diabetes. In 2019, diabetes was the
direct cause of 1.5 million deaths and 48% of all deaths due to diabetes occurred before the age of 70
years. Another 460 000 kidney disease deaths were caused by diabetes, and raised blood glucose causes
around 20% of cardiovascular deaths.
In recent decades, India has witnessed a rapidly exploding epidemic of diabetes. India today has the
second largest number of people with diabetes in the world. The International Diabetes Federation (IDF)
estimates that there are 72.9 million people with diabetes in India in 2017, which is projected to rise to
134.3 million by the year 2045. The prevalence of diabetes in urban India, especially in large
metropolitan cities has increased from 2% in the 1970s to over 20% at present and the rural areas are
also fast catching up.
Diabetes can be treated and its consequences avoided or delayed with diet, physical activity, medication
and regular screening and treatment for complications. A healthy diet, regular physical activity,
maintaining a normal body weight and avoiding tobacco use are ways to prevent or delay the onset of
type 2 diabetes.
2. Classification & Types of Diabetes:
➢ Type 1 Diabetes: Type 1 diabetes (previously known as insulin-dependent, juvenile or childhood-
onset) is characterized by deficient insulin production and requires daily administration of insulin. In
2017 there were 9 million people with type 1 diabetes worldwide. The majority of them live in high-
income countries. Neither its cause nor the means to prevent it are known. Symptoms include
excessive excretion of urine (polyuria), thirst (polydipsia), constant hunger, weight loss, vision
changes, and fatigue. These symptoms may occur suddenly.
➢ Type 2 Diabetes: Type 2 diabetes (formerly called non-insulin-dependent, or adult-onset) results from
the body’s ineffective use of insulin. More than 95% of people with diabetes have type 2 diabetes.
This type of diabetes is largely the result of excess body weight and physical inactivity. Symptoms
may be similar to those of type 1 diabetes but are often less marked. As a result, the disease may be
diagnosed several years after onset, after complications have already arisen. Until recently, this type
of diabetes was seen only in adults but it is now also occurring increasingly frequently in children.
➢ Gestational Diabetes: Gestational diabetes is hyperglycaemia with blood glucose values above
normal but below those diagnostics of diabetes. Gestational diabetes occurs during pregnancy.
Women with gestational diabetes are at an increased risk of complications during pregnancy and at
delivery. These women and possibly their children are also at increased risk of type 2 diabetes in the
future. Gestational diabetes is diagnosed through prenatal screening, rather than through reported
symptoms.
➢ Other types of Diabetes: Monogenic diabetes, pancreatic diabetes, drug-induced diabetes etc.
➢ Prediabetes: The term “prediabetes” refers to a situation where the blood glucose levels are higher
than normal, but not high enough to warrant a diagnosis of diabetes. Prediabetes consists of two
entities viz. impaired fasting glucose (IFG) and impaired glucose tolerance (IGT). The diagnostic
criteria for diabetes and prediabetes are summarized in Diagnostic criteria for diabetes and
prediabetes:
Symptoms of Diabetes:
1. Osmotic Symptoms- Polyuria, Polydipsia
2. Weight loss in spite of polyphagia
3. Tiredness, weakness
4. Generalised pruritus
5. Recurrent urogenital infections
6. Delayed healing of wounds
7. More than half of all patients with diabetes will have no symptoms at all
3. Diagnostic Criteria for Diabetes & Prediabetes:
Parameter Normoglycemia Prediabetes Diabetes
FPG < 100 (mg/dl) 100 – 125 (mg/dl) ≥ 126 (mg/dl)
2 Hrs PPG < 140 (mg/dl) 140 – 199 (mg/dl) ≥ 200 (mg/dl)
RPG - - ≥ 200 (mg/dl)
HbA1c < 5.7 % 5.7 – 6.4 % ≥ 6.5 %
Source: ADA - American Diabetes Association
FPG - Fasting Plasma Glucose; 2 Hrs PPG – 2 hours post prandial glucose test; HbA1c – Glycosylated Haemoglobin
Risk Factors for Type 2 Diabetes:
1. Age: The risk of type 2 diabetes increases as you get older, especially after age 35.
2. Weight: Being overweight or obese is a main risk.
3. Fat distribution: Storing fat mainly in your abdomen rather than your hips and thighs indicates a
greater risk.
4. Sedentary lifestyle: The less active you are, the greater your risk. Physical activity helps control your
weight, uses up glucose as energy and makes your cells more sensitive to insulin.
5. Family history: The risk of type 2 diabetes increases if your parent or sibling has type 2 diabetes.
6. Race and ethnicity: Although it's unclear why, people of certain races and ethnicities including Black,
Hispanic, Native American and Asian people, and Pacific Islanders are more likely to develop type 2
diabetes than white people are.
7. Blood lipid levels: An increased risk is associated with low levels of high-density lipoprotein (HDL)
cholesterol, the "good" cholesterol and high levels of triglycerides.
8. Prediabetes: Prediabetes is a condition in which your blood sugar level is higher than normal, but not
high enough to be classified as diabetes. If left untreated, prediabetes often progresses to type 2
diabetes.
9. Pregnancy-related risks: Your risk of developing type 2 diabetes increases if you developed
gestational diabetes when you were pregnant or if you gave birth to a baby weighing more than 4
kilograms.
10. Polycystic ovary syndrome: Having polycystic ovary syndrome, a common condition characterized by
irregular menstrual periods, excess hair growth and obesity increases the risk of diabetes
11. Hypertension: People with high blood pressure usually have insulin resistance and have an increased
risk of developing type 2 diabetes.
12. Smoking: Smoking is associated with a higher risk of type 2 diabetes, and also increases the risk of
other health conditions such as heart disease and cancer.
13. Mental health conditions: Certain mental health conditions including schizophrenia, bipolar disorder,
depression are also risk factors for type 2 diabetes.
14. Alcohol: Drinking too much alcohol is associated with an increased risk of type 2 diabetes. Current
guidelines recommend not regularly drinking more than 14 units per week and that these units should
be spread evenly over 3-4 days.
15. Sleep: If you have disturbed sleep this can be associated with an increased the risk of type 2 diabetes.
Not getting enough sleep, or sleeping for too long have been associated with an increased risk. Many
things can affect how long and how well we sleep.
4. Type 2 Diabetes is Preventable:
Lifestyle measures have been shown to be effective in preventing or delaying the onset of type 2 diabetes.
To help prevent type 2 diabetes and its complications, people should:
Achieve and maintain a healthy body weight, be physically active, doing at least 30 minutes of regular,
moderate intensity activity on most days. More activity is required for weight control, eat a healthy diet,
avoiding sugar and saturated fats, and avoid tobacco use stop smoking.
Pathophysiology of T2DM & The Ominous Octet:
Blood glucose levels in human body are determined by several factors. In his 2008 Banting lecture to the ADA
68th Scientific Sessions, Prof Ralph DeFronzo proposed an “ominous octet” of eight factors that contributed
to the pathophysiology of type 2 diabetes. The identification of these 8 defects has significant implications
for treating T2DM. On the other hand, to achieve effective treatment and be relieved from diabetes, lifestyle
changes and proper medication should be used to correct these 8 pathophysiological defects.
1. Decreased insulin secretion:
✓ Your pancreas works 24/7. Once impaired glucose tolerance (inability to correct blood sugar
to normal levels) is present, 80% of your pancreas’ function is also affected. Over time, your
pancreas gets tired and stops producing insulin. This may result to you being considered as
insulin dependent.
5. 2. Increased Glucagon Secretion:
✓ Your pancreas has beta cells that produce insulin and alpha cells that produce glucagon.
Glucagon causes your liver to breakdown glycogen for energy demand. It is counteracted by
insulin. If insulin is impaired, so is the regulation of blood sugar, leading to even higher glucose
levels.
3. Increased Hepatic Glucose Production (HGP):
✓ Your liver undergoes two processes called gluconeogenesis (generation of glucose from
certain non-carbohydrate carbon substrates) and glycogenolysis (glycogen is broken down
into glucose to provide immediate energy and to maintain blood glucose levels during
fasting). In diabetes, even when your blood glucose is already high, your liver continues to
release more glucose, which results to hyperglycemia.
4. Decreased Incretin Effect:
✓ Our intestines also play another important role apart from regulating our digestion. Incretins
are hormones that come from your intestines. In T2DM, there is a deficiency of GLP-1 (a
hormone that plays important roles in regulating appetite and blood sugar levels) and
resistance to the action of GIP (a hormone that regulates glucose and lipid metabolism).
5. Increased Lipolysis:
✓ This happens when there is increased fat breakdown in your body. The fat cells in your body
release more free fatty acids where excess lipid may also accumulate in your liver, muscles,
and pancreas. This worsens overall insulin resistance and decreases insulin secretion.
6. Increased Glucose Reabsorption:
✓ Your kidneys help hold down the glucose it filters, which is critical in providing for the energy
demands of your body’s tissues. However, in diabetes, your kidneys hold on to most of the
glucose, even if the glucose levels are already high.
7. Decreased Glucose Uptake by Muscles:
✓ This happens when your muscle cells have decreased ability to take up glucose and remove it
from your bloodstream. This leaves the glucose to float around your bloodstream, which
often leads to blood sugar spiking up.
8. Neurotransmitter Dysfunction:
✓ Neurotransmitters are natural chemicals that stimulate your brain and nervous system. When
these signals are disrupted, appetite increases which may result to obesity and a spike in Type
2 diabetes cases.
6. Management of Type 2 Diabetes Millitus:
Managing blood glucose in type 2 diabetes involves a mixed approach of lifestyle changes and
pharmacological therapy. Therapy begins with education, then a reduction of sugar & fat in
diet and an increase in exercise. If control remains inadequate, the usual next step is, starting
medication to control blood sugar.
Lifestyle Management:
1. Dietary Approach to manage T2DM:
➢ Energy or Calorie: Attain or maintain a reasonable body weight is important in management of
T2DM.
o Ideal Body Weight (IBW) = (Height in cm – 100) * 0.90
o Approximately, 25 kcals/kg ideal body weight/day can be given to a moderately active
patient with diabetes.
➢ Energy or Calorie Distribution:
o Carbohydrates: 50 % of energy from carbohydrates is an ideal recommendation.
Carbohydrates should be complex in nature. It is recommended that carbohydrates from
foods high in fibre e.g., whole grains (unpolished cereals and millets), legumes, peas, beans,
oats, barley and some fruits with low glycemic index and glycemic load should be consumed.
All patients with diabetes should be encouraged to take 6 small meals a day.
o Fibre: Fibre recommendation for general population is 40 g/day (2000 Kcals). Traditional
Indian diets that include whole grains along with whole pulses like grams, soy, green leafy
vegetables and some fruits is the recommendation. Fruits like papaya, guava, apples, pears,
oranges, mosambi can be taken in moderation. All fruit juices are best avoided.
o Proteins: Proteins should provide 12-15 % of the total energy intake for people with diabetes
similar to the recommendations for the general population. Proteins from vegetable sources
like pulses, soy, grams, peas as well as form low fat milk, low fat curds, fish and lean meats
are recommended.
o Fats: Fats should provide 20-30 % of total energy intake for people with diabetes. Evidence is
inconclusive for an ideal amount of total fat intake for people with diabetes, therefore, goals
should be individualized. Fat quality is as important as the quantity. Monounsaturated Fatty
Acids or MUFA-rich cooking oils like mustard, rice bran, peanut (groundnut) and gingelly are
recommended.
7. o Salt: Sodium intake recommendations for people with diabetes are the same as that for the
general population. Added (iodized) salt should be less than 5 g/day. For persons with
hypertension and diabetes, the intake should be reduced to less than 3 g/ day.
o Alcohol: It is best to avoid alcohol, however if used, should be taken in moderation. If alcohol
is consumed, it should not be counted as part of the meal plan. However, it should be borne
in mind that alcohol does provide calories (7 kcal/ g), which are considered as “empty
calories”. Alcohol can further exacerbate fatty liver, neuropathy, dyslipidaemia, obesity and
also worsen blood glucose levels.
o Sweeteners: Nutritive Sweeteners including fructose, honey, corn syrup, molasses, fruit juice
or dextrose, maltose, mannitol, sorbitol and xylitol. All these are best avoided. Non-nutritive
Sweeteners like Aspartame, acesulfame K, stevia, sucralose and saccharin are currently
approved for use. However, they should be used in moderation.
o Tobacco: Smoking and tobacco chewing is totally prohibited.
2. Physical Activity and Exercise:
➢ Regular physical activity along with regulated exercise is an essential component of management of
type 2 diabetes. Complete evaluation of patients with diabetes should be performed before
recommending an exercise program. The exercise program has to be individualized according to one’s
ability and individual capacity. Benefits of exercise:
o Improves insulin sensitivity, reduces the risk of heart disease, high blood pressure, bone
diseases, and unhealthy weight gain.
o Keeps one flexible and agile.
o Helps relieve stress, anxiety and prevents depression.
o Increases strength and stamina.
o Promotes sound sleep.
o Increases metabolic rate and digestion.
o Lowers lipids.
o Delays the process of aging
Recommendation is about 150 minutes of aerobic activity or its equivalent /week along with some
resistance training at least twice a week and flexibility exercises. People with diabetes need an extra
quick acting carbohydrate snack before the exercise and during the exercise if the exercise period
extends the daily-recommended routine.
➢ Stress: Stress management is essential which could take the form of meditation, yoga, a long outdoor
walk, exercise and trying out hobbies like reading, gardening, painting etc. Practice of yoga is our
traditional Indian system, which has therapeutic value in controlling our physical and mental health.
It should be done under the guidance of an expert.
8. Pharmacological Management:
Blood glucose levels are determined by several factors such as absorption of glucose from gut, uptake of
glucose by peripheral tissues, hepatic glucose output, and secretion of hormones such as insulin and
glucagon from the pancreas and incretins from the gut, as well as renal handling of glucose. Various anti-
hyperglycemic agents act by modifying the factors aiding in the control of hyperglycaemia.
Pharmacological therapy is divided into:
1. Oral anti-hyperglycaemic drugs
2. Insulin therapy
3. Non-insulin injectable therapy
1. Oral Anti-Hyperglycaemic Drugs:
Biguanides: (Metformin)
• Mode of Action: It mediates its effect by enhancing sensitivity of the liver and peripheral tissues
to circulating insulin. Biguanides are considered to increase insulin sensitivity in vivo, resulting in
reduced plasma glucose concentrations, increased glucose uptake, and decreased
gluconeogenesis. However, in hyperinsulinemia, biguanides can lower fasting levels of insulin in
plasma. Their therapeutic uses derive from their tendency to reduce gluconeogenesis in the liver,
and, as a result, reduce the level of glucose in the blood. Biguanides also tend to make the cells
of the body more willing to absorb glucose already present in the bloodstream, and there again
reducing the level of glucose in the plasma.
• Side Effects: Gastrointestinal side effects like abdominal discomfort and diarrhoea may occur in
some patients. Prolonged use of metformin may be associated with vitamin B12 deficiency.
Ominous Octet Biguanide Sulfonylurea
DPP-4
Inhibitors
SGLT-2
Inhibitors
α-Glucosidase
Inhibitors
Glinides
Thiazoli-
dinediones
GLP-1
RA
Decreased Insulin
Secretion √ √ √ √
Increased Glucagon
Secretion √ √
Increased Hepatic
Glucose Production √ √
Decreased Incretin
Effect √ √ √ √
Increased Lipolysis √
Increased Glucose
Reabsorption √
Decreased Glucose
Uptake by Muscles √ √
Neurotransmitter
Dysfunction √
9. Sulphonylureas: (Glimepiride, Glibenclamide, Glibornuride, Gliclazide, Glipizide, Gliquidone)
• Mode of Action: Sulfonylureas bind to and close ATP-sensitive K+ (KATP) channels on the cell
membrane of pancreatic beta cells, which depolarizes the cell by preventing potassium from
exiting. This depolarization opens voltage-gated Ca2+ channels. The rise in intracellular calcium
leads to increased fusion of insulin granules with the cell membrane, and therefore increased
secretion of mature insulin.
• Side Effects: Weight gain Hypoglycaemia.
Dipeptidyl Peptidase-4 (DPP-4) Inhibitors: (Sitagliptin, Vildagliptin, Saxagliptin, Linagliptin,
Teneligliptin & Gemigliptin)
• Mode of Action: These agents work by inhibiting the enzyme dipeptidyl peptidase-4, which
breaks down the incretin hormones glucagon-like peptide 1 (GLP-1) and glucose dependent
insulinotropic peptide (GIP) secreted from the gut in response to a meal. Increase in blood levels
of incretin hormones stimulates glucose-dependent insulin secretion from the beta cells of the
pancreas and suppression of glucagon release from the alpha cells.
• Side Effects: Gastrointestinal problems including nausea, diarrhoea and stomach pain Skin
reactions painful skin followed by a red or purple rash Joint pains.
SGLT2 Inhibitors (Sodium Glucose Transporter 2 Inhibitors): (Canagliflozin, Dapagliflozin &
Empagliflozin Remogliflozin)
• Mode of Action: They inhibit SGLT2 located on the proximal convoluted tubule in the kidney.
SGLT2 is the major transport protein and promotes reabsorption from the glomerular filtration
glucose back into circulation and is responsible for approximately 90% of the kidney's glucose
reabsorption. By inhibiting SGLT2, gliflozins prevent the kidneys' reuptake of glucose from the
glomerular filtrate and subsequently lower the glucose level in the blood and promote the
excretion of glucose in the urine (glucosuria). In addition to reducing blood glucose levels, these
agents also cause weight loss and reduction of blood pressure. There is also some evidence that
these agents have cardiovascular benefits over and above their glucose lowering effects.
• Side Effects: Genital mycotic infections Urinary tract infections.
Thiazolidinediones (Glitazones): (Pioglitazone)
• Mode of Action: It is an insulin sensitizer at adipose tissue and skeletal muscle. This effect is
brought about by its binding to nuclear peroxisome proliferator activated receptor-gamma
(PPAR-y). It also inhibits hepatic glucose output. Pioglitazone has partial PPAR-alpha agonist
activity, which accounts for its beneficial effects on lipid profile.
• Side Effects: Weight gain may be quite significant and is dose- related Edema and cardiac failure
are reported especially when combined with insulin
10. Glinides (Non-Sulphonylurea Insulin Secretagogues): (Repaglinide & Nateglinide)
• Mode of Action: Glinides are benzoic acid derivatives, which act on separate non-sulphonylurea
receptor binding sites on the β-cell and enhance insulin secretion. These agents are absorbed
rapidly (0.5-1 hr) and have a short half-life (<1 hr). Thus, they result in rapid but brief release of
insulin, and hence may be useful in managing postprandial hyperglycaemia. They have to be
administered with each meal.
• Side Effects: Hypoglycaemia.
Alpha-Glucosidase Inhibitors: (Acarbose, Miglitol & Voglibose)
• Mode of Action: Alpha- glucosidase inhibitors (AGI) act by competitively inhibiting alpha-
glucosidase, the enzyme in the small intestine brush border which breaks down oligosaccharides
and disaccharides into mono-saccharides. Thus, the absorption of glucose is delayed. AGIs are
especially useful in decreasing post-prandial glucose levels.
• Side Effects: Gastrointestinal side effects like bloating, abdominal discomfort, diarrhoea and
flatulence.
Insulin Therapy:
Insulin is the mainstay of therapy in type 1 diabetes. However, many patients with type 2 diabetes will
also require insulin injections to help them achieve their glycemic targets.
Indications for the use of insulin in type 2 diabetes mellitus at the time of diagnosis:
• Person with diabetes with significant, symptomatic hyperglycaemia, loss of weight and polyuria,
polydipsia, polyphagia.
• Fasting plasma glucose > 270 mg/dl or HbA1c >9%.
• Severe infections.
• Presence of ketosis.
Other situations where insulin is indicated:
• Patients not responding to optimal doses of oral anti-hyperglycaemic agents alone or in
combination.
• Acute hyperglycaemia, diabetic ketoacidosis / hyperglycemic-hyperosmolar state / lactic acidosis.
• Stressful situations such as acute myocardial infarction, stroke, acute infections, tuberculosis,
trauma and other conditions requiring hospitalisation.
• Pregnancy and lactation.
• Peri-operative state.
• Intolerant / contraindications to OHA.
• Hepatic and renal failure.
• Person with diabetes on steroids.
11. Types Of Insulin Preparations:
Different types of insulin are available. They have different pharmacokinetic properties. Insulin type,
injection technique, insulin antibodies, site of injection and individual patient response differences
can affect the onset, degree and duration of insulin activity. Human insulin manufactured by rDNA
technology and insulin analogues are the only insulins available at present. Animal insulin is no
longer available.
• Human insulin:
o Short acting – human soluble insulin (regular).
o Intermediate acting – neutral protamine Hagedorn (NPH).
o Premixed- mixtures of regular and NPH insulin in 25/75, 30/70, 50/50 proportion.
• Insulin Analogues:
o Rapid acting (e.g., Lispro, Aspart, Glulisine).
o Long acting (Glargine, Degludec, Detemir).
o Premixed Insulin analogue (Lispro/ lispro protamine, aspart/ aspart protamine).
o Co-formulations (Degludec + Aspart insulin).
o Insulin degludec/insulin aspart (IDegAsp) is a soluble formulation of the novel basal
analogue insulin degludec(70%) and insulin aspart (IAsp: 30%).
3. Non-Insulin Injectable Therapy:
GLP-1 Receptor Agonists: (Exenatide, Liraglutide, Lixisenatide & Dulaglutide)
• Mode of Action: The incretin hormones glucagon-like peptide 1 (GLP-1) and glucose
dependent insulinotropic peptide (GIP) are secreted from the gut in response to a meal and
bring about glucose-dependent insulin secretion from the beta cells of the pancreas and
suppression of glucagon release from the alpha cells. The GLP-1 receptor analogues currently
available are resistant to degradation by the DPP-4 enzyme and hence have longer half-lives
than native GLP-1. The main advantages of these agents are that they reduce hyperglycaemia
with minimal risk of hypoglycaemia and also promote weight loss. There is some evidence
that these agents improve cardiovascular outcomes over and beyond their effects on blood
glucose.
• Side Effects: The main side effects are nausea and vomiting; a few cases of acute pancreatitis
have also been reported. They can be combined with all other classes of anti-hyperglycaemic
agents except the DPP-4 inhibitors.
12. Complications of Diabetes:
Most of the morbidity and mortality due to diabetes arises on account of its complications. Diabetes
complications can be broadly divided into acute and chronic complications. Acute complications
include hypo- and hyperglycaemic emergencies whereas chronic complications include
microvascular disease (retinopathy, nephropathy and neuropathy), macrovascular disease (coronary
artery disease, cerebrovascular disease and peripheral vascular disease) and diabetic foot.
Acute Complications:
Hypoglycaemia: It is a common side effect due to drug therapy of diabetes especially Sulphonylureas
and insulin. The patient may have classical symptoms like hunger, sweating, tremors, palpitation
with or without loss of consciousness.
Hyperglycaemic emergencies (Diabetic Ketoacidosis or Hyperosmolar Hyperglycaemic State):
Usually such emergencies occur in situations like infections or other stressful conditions. There is
usual history of missed dose of insulin or poor control of diabetes. DKA is characterized by abdominal
pain and is manifested with breathlessness, vomiting, altered sensorium and dehydration. The
symptoms of HHS are predominantly neurological; dehydration is usually more profound but
abdominal pain is uncommon.
Chronic Complications:
Diabetes mellitus is a systemic disorder, which potentially can cause serious organ damage involving
eyes, heart, kidney, nerves and limbs, which ultimately can lead to blindness, heart attack, kidney
failure and limb amputation respectively. If diagnosed early and treated in time appropriately, the
damage to some of these organs can be largely prevented or reversed. Another important issue is
that most complications cause clinical symptoms only at a very late stage and thus for their early
diagnosis, these complications have to be specifically looked for even at the time of prediabetes.
Considering this, the following approach is advisable for management of people with type 2
diabetes.
