This presentation holds information on diabetes its types, it's diagnosis, and it's management.

1. ANTIDIABETIC DRUGS
Dr NOOPUR VERMA

2. PANCREASE
• The endocrine pancreas in the adult human
consists of approximately 1 million islets of
Langerhans interspersed throughout the
pancreatic gland
• Within the islets, at least five hormone
producing cells are present

3. PANCREATIC HORMONES
• INSULIN-the storage and anabolic hormone of the body;
• ISLET AMYLOID POLYPEPTIDE (IAPP, OR AMYLIN)- which modulates appetite, gastric emptying, and
glucagon and insulin secretion;
• GLUCAGON- the hyperglycemic factor that mobilizes glycogen stores;
• SOMATOSTATIN- a universal inhibitor of secretory cells;
• PANCREATIC PEPTIDE- a small protein that facilitates digestive processes by a mechanism not yet
clarified
• GHRELIN- a peptide known to increase pituitary growth hormone release

4. INSULIN
• Molecular weight in humans of 5808
• It contains 51 amino acids arranged in two chains (A
and B)
• Proinsulin, a long single-chain protein molecule, is
processed within the Golgi apparatus of beta cells and
packaged into granules, where it is hydrolyzed into
insulin and a residual connecting segment called C-
peptide by removal of four amino acids
• Insulin and C-peptide are secreted in equimolar
amounts in response to all insulin secretagogues

5. INSULIN SECRETION
• Insulin is released from pancreatic beta
cells at a low basal rate and at a much
higher stimulated rate in response to a
variety of stimuli, especially glucose
• Other -sugars (eg, mannose), amino
acids( eg, leucine, arginine), hormones
such as (GLP-1), (GIP), glucagon,
cholecystokinin, high concentrations of
fatty acids, and β-adrenergic
sympathetic activity

6. INSULIN RELEASE AND EFFECTS

8. • Basal serum insulin values of 5–15
μU/mL (30–90 pmol/L) are found in
normal humans, with a peak rise to
60–90 μU/mL (360–540 pmol/L)
during meals.
• After insulin has entered the
circulation, it diffuses into tissues,
where it is bound by specialized
receptors that are found on the
membranes of most tissues

9. GLUCAGON
• Glucagon is synthesized in the alpha cells of the pancreatic islets of Langerhans
• Glucagon is extensively degraded in the liver and kidney as well as in plasma and at its tissue
receptor sites. Its half-life in plasma is between 3 and 6 minutes, which is similar to that of
insulin
• The first six amino acids at the amino terminal of the glucagon molecule bind to specific Gs
protein–coupled receptors on liver cells. This leads to an increase in cAMP, which facilitates
catabolism of stored glycogen and increases gluconeogenesis and ketogenesis. The immediate
pharmacological result of glucagon infusion is to raise blood glucose at the expense of stored
hepatic glycogen

10. GLUCAGON
• Glucagon has a potent inotropic and chronotropic effect on the heart, mediated by the cAMP mechanism
• A. Severe Hypoglycemia
• B. Endocrine Diagnosis
• C. Beta-Adrenoceptor Blocker Overdose
• D. Radiology of the Bowel
• S/E- Transient nausea and occasional vomiting can result from glucagon administration. It should not be used in a
patient with pheochromocytoma

12. DIABETES MELLITUS

13. • Diabetes mellitus is defined as an elevated blood glucose associated with absent
or inadequate pancreatic insulin secretion, with or without concurrent
impairment of insulin action
• type 1, type 2, other, and gestational diabetes mellitus

14. Type 1 Diabetes Mellitus
• The hallmark of type 1 diabetes is selective beta cell (B cell) destruction and
severe or absolute insulin deficiency
• Type 1 diabetes is further subdivided into immune-mediated (type 1a) and
idiopathic causes (type 1b)
• Most patients are younger than 30 years of age at the time of diagnosis, the
onset can occur at any age
• They can be treated at first with oral hypoglycemic agents but then need
insulin as their beta cell function declines.

15. Type 2 Diabetes Mellitus
• Heterogenous group of conditions characterized by tissue resistance to the
action of insulin combined with a relative deficiency in insulin secretion
• Although the circulating endogenous insulin is sufficient to prevent
ketoacidosis, it is inadequate to prevent hyperglycemia. Patients with type 2
diabetes can initially be controlled with diet, exercise and oral glucose
lowering agents or non-insulin injectables. Some patients have progressive
beta cell failure and eventually may also need insulin therapy

16. MEDICATIONS FOR
HYPERGLYCEMIA

17. INSULIN PREPARATIONS
• Human insulin is dispensed as regular (R) and neutral protamine hagedorn (NPH) formulations
• There are also six analogs of human insulin.
• Three of the analogs are rapidly acting: insulin lispro, insulin aspart, and insulin glulisine
• Three are long acting: insulin glargine, insulin detemir, and insulin degludec
• Several insulins are also available at higher concentrations in the prefilled disposable pen
form: insulin glargine 300 units/mL (U300); insulin degludec (U200); insulin lispro 200
units/mL (U200); and regular insulin 500 units/mL (U500)

21. INSULIN DELIVERY SYSTEMS
• A. Insulin Syringes and Needles-Disposable plastic syringes with needles
attached are available in 1-mL (100 units), 0.5-mL (50 units), and 0.3-mL (30
units) sizes. The “low-dose” 0.3-mL syringes are popular because many
patients with diabetes do not take more than 30 Units
• B. Insulin Pens-Cartridges of insulin lispro, insulin aspart, and insulin glargine
are available for reusable pens
• C. Continuous Subcutaneous Insulin Infusion Devices (CSII, Insulin Pumps)
• D. Inhaled Insulin

22. Immunopathology of Insulin
Therapy
• 1. Insulin allergy—Insulin allergy, an immediate type hypersensitivity, is a rare condition in
which local or systemic urticaria results from histamine release from tissue mast cells
sensitized by anti-insulin IgE antibodies. In severe cases, anaphylaxis results.
• 2. Immune insulin resistance—A low titer of circulating IgG anti-insulin antibodies that
neutralize the action of insulin to a negligible extent develops in most insulin-treated patients.
Rarely, the titer of insulin antibodies leads to insulin resistance and may be associated with
other systemic autoimmune processes such as lupus erythematosus
• Lipodystrophy at Injection Sites-Injection of animal insulin preparations sometimes led to
atrophy of subcutaneous fatty tissue at the site of injection

23. GLP-1 RECEPTOR AGONISTS
• GLP-1 is an important incretin released from the gut in response to ingested
glucose
• induces insulin release from pancreatic β cells
• inhibits glucagon release from α cells
• slows gastric emptying and suppresses appetite by activating specific GLP-1
receptors, which are cell surface gpcrs
• GLP-1 itself is not suitable for clinical use because of rapid degradation by the
enzyme dipeptidyl peptidase-4 (DPP-4)

24. GLP-1 RECEPTOR AGONISTS
• EXENATIDE It is a synthetic DPP-4 resistant analogue which activates GLP-1 receptors
• Inactive orally
• s.c. injection its plasma t½ is ~ 3 hours and duration of action 6–10 hours.
• Injected s.c. before breakfast and dinner, it is used as add-on drug
• Acute pancreatitis is a risk.
• Dose: initially 5 µg s.c. before breakfast and dinner; increase to 10 µg BD if needed.

25. GLP-1 RECEPTOR AGONISTS
• LIRAGLUTIDE- longer-acting GLP-1 agonist
• its tight binding to plasma proteins extends t½ to > 12 hours and duration of action to > 24 hours
• Injected s.c. once daily, alone or added to oral metformin ± SU or pioglitazone
• Nausea and diarrhoea are the frequent side effects
• weight loss and it is approved for use in obesity
• Albiglutide and dulaglutide are very long acting GLP-1 receptor agonists which need to be injected once weekly.
• PRAMLINTIDE- s.c. injection before meal, anorectic action
• The duration of action is 2–3 hours. both type 1 and type 2 diabetes Hypoglycaemia is the most important adverse
effect. Loss of appetite, nausea and vomiting are the other side effects. Reduction in body weight is an additional
benefit

27. SULFONYLUREAS
• The major action of sulfonylureas is to increase insulin release from the pancreas
• They bind to a high affinity sulfonylurea receptor that is associated with a beta-cell inward
rectifier ATP-sensitive potassium channel
• Binding of a sulfonylurea inhibits the efflux of potassium ions through the channel and results
in depolarization.
• Depolarization opens a voltage-gated calcium channel and results in calcium influx and the
release of preformed insulin

28. PHARMACOKINETICS
• A-All SUs are well absorbed orally, and are
• D-90% or more bound to plasma proteins: have low volumes of distribution (0.2–0.4 L/kg).
• M-They are primarily metabolized— may produce active metabolite.
• E- The metabolites (active/inactive) are excreted in urine.
• As such, they should be used cautiously in patients with liver or kidney dysfunction.
• After few months of administration, the insulinaemic action of SUs declines, down regulation of sulfonylurea
receptors (SUR1) on β cells, but improvement in glucose tolerance is maintained

29. Meglitinide/D-phenylalanine analogues (Katp
Channel blockers)
• These are KATP channel blockers with a quick and short lasting insulinemic action
• Repaglinide- binding to SUR → closure of ATP sensitive K+ channels → depolarisation → insulin release
• Repaglinide is quickly absorbed and rapidly metabolized. It induces fast onset short-lasting insulin
release
• It is administered before each major meal to control postprandial hyperglycaemia. dose should be
omitted if a meal is missed
• Side effects are mild headache, dyspepsia, arthralgia and weight gain
• Nateglinide- Ingested 10 min before meal, Episodes of hypoglycaemia are less frequent than with Sus
• Side effects are dizziness, nausea, flu-like symptoms and joint pain. used in type 2 DM along with other
antidiabetics, to control postprandial rise in blood glucose

30. Dipeptidyl peptidase-4 (DPP-4) inhibitors
• DPP-4 in rapid degradation of endogenous GLP-1
• orally active inhibitors of this enzyme have been developed as indirectly acting insulin secretagogues
• their blood sugar lowering efficacy is moderate compared to that of SU
• SITAGLIPTIN - This is the first DPP-4 inhibitor introduced in 2006. It is a competitive and selective DPP-4 inhibitor
which potentiates the action of GLP-1 and GIP, boosts postprandial insulin release, decreases glucagon secretion and
lowers meal-time as well as fasting blood glucose in type 2 diabetics.
• DPP-4 inhibitors primarily as adjuvant drugs in type 2 diabetics not well controlled by metformin/SUs/pioglitazone or
insulin
• Sitagliptin is well absorbed orally, is little metabolized and is largely excreted unchanged in urine with a t½ averaging
12 hours. Dose reduction is needed in renal impairment, but not in liver disease. Sitagliptin is well tolerated, though
nausea may occur, it is not prominent as in the case of GLP-1 agonists

31. • Side effects are nausea, loose stools, headache, rashes, allergic reactions including some serious ones like,
angioedema, exfoliative dermatitis and edema. Nasopharyngitis and cough occurs in some patients.
• VILDAGLIPTIN- This DPP-4 inhibitor binds to the enzyme covalently. The complex dissociates very slowly resulting in
persistent DPP-4 inhibition even after the free drug has been cleared from circulation. This explains the longer
duration of action (12–24 hours) despite short plasma t½ (2–4 hours)
• The major route of elimination is by hepatic metabolism; only 20–25% is excreted unchanged in urine. Dose reduction
is needed in moderately severe liver and kidney disease. Vildagliptin is less selective than sitagliptin. may require
twice daily dosing
• SAXAGLIPTIN Like vildagliptin, saxagliptin binds covalently with DPP-4 and acts for 24 hours despite a plasma t½ of 2–
4 hours

32. • TENELIGLIPTIN It is a new DPP-4 inhibitor developed in Japan which exerts long-lasting (>24 hours) DPP-4 inhibition
and antiglycaemic effect. Following a single morning dose, postprandial hyperglycaemia is suppressed at all 3 meals of
the day.
• Metabolites of teneligliptin are excreted by both liver and kidney;
• no dose reduction is needed in patients with renal impairment.
• No cardiovascular adverse effects have been noted, caution is to be exercised in patients prone to QT prolongation.

33. BIGUANIDE (AMPK ACTIVATOR)
• Two biguanide antidiabetics, phenformin and metformin were introduced in the 1950s. Because of higher risk of lactic
acidosis, phenformin has been banned in India since 2003
• METFORMIN It differs markedly from SUs: first choice drug for all type 2 DM patients, except when not tolerated or contraindicated.
• causes little or no hypoglycaemia in nondiabetic subjects, and even in diabetics, hypoglycaemia is rare.
• ‘euglycaemic’, rather than hypoglycaemic’.
• It does not stimulate pancreatic β cells.
• Metformin is reported to improve lipid profile as well in type 2 diabetics.
• Mechanism of action - do not cause insulin release, but presence of insulin is essential for their action. activation of
AMP-dependent protein kinase (AMPK) to play a crucial role in mediating the actions of metformin

34. METFORMIN
• 1. Suppresses hepatic gluconeogenesis and glucose output from liver. This is the major action
responsible for lowering of blood glucose in diabetics.
• 2. Enhances insulin-mediated glucose uptake and disposal in skeletal muscle and fat. Insulin
resistance exhibited by type-2 diabetics is thus overcome. This translates into— glycogen
storage in skeletal muscle – reduced lipogenesis in adipose tissue and enhanced fatty acid
oxidation.
• 3. Interferes with mitochondrial respiratory chain and promotes peripheral glucose utilization
through anaerobic glycolysis.
• P/K- well absorbed orally, not metabolized, unchanged by kidney in renal failure and
increases the risk of lactic acidosis

35. METFORMIN- advantages
• antihyperglycaemic, but not hypoglycaemic
• weight loss promoting
• has potential to prevent macrovascular as well as microvascular complications of diabetes
• no acceleration of β cell exhaustion/ failure in type 2 DM.
• antihyperglycaemic efficacy (HbA1c reduction by 0.8–1.2%) equivalent to other oral drugs.
• can be combined with any other oral or injectable antidiabetic.
• can prevent new onset type 2 DM in obese, middle aged subjects with impaired glucose
tolerance
• Infertility: Metformin has been found to improve ovulation and fertility in some infertile
women with polycystic ovary

36. Thiazolidinedione (PPARγ agonist)
• PIOGLITAZONE- ONLY MEMBER
• This class of oral antidiabetic drugs are selective agonists for the nuclear peroxisome proliferator-activated receptor γ
(PPARγ) which is expressed mainly in fat cells, but also in muscle and some other cells.
• . Entry of glucose into muscle and fat is improved
• the primary action is to enhance peripheral insulin sensitivity.
• Activation of genes regulating fatty acid metabolism and lipogenesis in adipose tissue contributes to the insulin
sensitizing action
• fatty tissue is a major site of their action

37. Thiazolidinedione (PPARγ agonist)
• Pioglitazone, in addition, lowers serum triglyceride level and raises HDL level without much
change in LDL level,
• Pioglitazone is well tolerated; adverse effects are plasma volume expansion, edema, weight
gain, headache, myalgia and mild anaemia
• Few cases of hepatic dysfunction have been reported; CHF may be precipitated or worsened.
Monitoring of liver function is advised
• Pioglitazone is contraindicated in liver disease and in CHF. Glitazones increase the risk of
fractures, especially in elderly women.
• Failure of oral contraception may occur during pioglitazone therapy

39. 𝛼Glucosidase inhibitors
• ACARBOSE It is a complex oligosaccharide which reversibly inhibits α-glucosidases, the final enzymes for the digestion
of carbohydrates in small intestine mucosa. GLP-1 release is promoted which may contribute to the effect
• It slows down and decreases digestion and absorption of polysaccharides (starch, etc.) and sucrose
• Acarbose is a mild antihyperglycaemic and not a hypoglycaemic;
• may be used as an adjuvant to diet (with or without metformin/SU) in obese diabetics.
• Acarbose 50–100 mg TDS is taken at the beginning of each major meal.
• Only a small fraction of the dose is absorbed. Flatulence, abdominal discomfort and loose stool are produced in about
50% patients due to fermentation of unabsorbed carbohydrates. Patient acceptability of α-glucosidase inhibitors is
poor due to uncomfortable g.i. symptoms.

40. 𝛼Glucosidase inhibitors
• MIGLITOL It has a smaller molecule than acarbose, and it is a stronger inhibitor of sucrase.
• Potency for other α-glucosidases is equivalent to acarbose.
• Absorption of miglitol is substantial, but variable. The absorbed drug is excreted by the kidney. No systemic toxicity is
known. Dose: 25–100 mg TDS at beginning of each meal.
• VOGLIBOSE Has properties, use and side effects similar to that of acarbose. Dose: 200–300 µg TDS just before meals.

41. DOPAMINE D2 AGONIST
• BROMOCRIPTINE- approved by US-FDA for adjunctive treatment of type 2 DM
• Taken early in the morning it is thought to act on the hypothalamic dopaminergic control of the circadian rhythm of
hormone release and reset it to reduce insulin resistance
• Bromocriptine can be taken alone to supplement diet+exercise or added to metformin or SU or both

42. Sodium-glucose co-transport-2 (SGLT-2)
inhibitor
• All the glucose filtered at the glomerulus is reabsorbed in the proximal tubules. The major transporter which
accomplishes this is SGLT-2, whose inhibition induces glucosuria and lowers blood glucose in type 2 DM, as well as
causes weight loss
• DAPAGLIFLOZIN, CANAGLIFLOZIN These SGLT-2 inhibitors are approved for use in type 2 DM patients.
• After once daily dosing, they produce round-the-clock glucosuria and lower blood glucose levels
• Used alone or in combination with other antidiabetic drugs, they reduce HbA1C levels by 0.5–1.0%, but do not cause
hypoglycaemia
• Glycosuria which can predispose to urinary and genital infections, electrolyte imbalance, ketoacidosis and increased
urinary frequency
• They are contraindicated in patients with renal insufficiency