This ppt is useful for UG MBBS, PG Pharmacology and any other person interested in Pharmacotherapy of Diabetes Mellitus.

1. PHARMACOLOGY OF
DIABETES MELLITUS
Dr. CHANDANE R. D.
Associate Professor
Dept. Of Pharmacology
Lady Hardinge Medical College
New Delhi

2. DIABETES MELLITUS
Group of syndromes characterized by
hyperglycemia; altered metabolism of lipid,
CHO & Proteins and increase risk of
complications from vascular diseases
Sushruta – ayurveda
Aeretaeus – Diabetes - first century
Dobson – sugar in urine 1755

3. Classification of Diabetes Mellitus
I) Type 1 DM ( IDDM )
a) Autoimmune (Type 1 A)
b) Non autoimmune/ idiopathic (Type 1 B)
II) Type 2 DM (NIDDM)
III) Type 3 DM (Other specific types of DM)
A) Specific defined gene mutation
a) Maturity onset diabetes of youth (MODY)
i) MODY-1: Hepatic nuclear factor 4α (HNF4A) gene mutation
ii) MODY-2: Glucokinase gene mutation
iii) MODY-3: Hepatic nuclear factor 1α gene mutation
iv) MODY-4: Insulin promotor factor 1 (IPF1) gene mutation
v) MODY-5: Hepatic nuclear factor 1β (HNF1B) gene mutation
vi) MODY-6: Neurogenic Differentiation 1(NEUROD1) gene mutation
vii) MODY-X: Unidentified gene mutation
b) Insulin gene mutation
c) Insulin receptor gene mutation

4. Classification…….
B) Diabetes Secondary to Pancreatic diseases
i) Chronic Pancreatitis
ii) Surgery
iii) Tropical Diabetes (Chronic Pancreatitis with nutritional/ toxic factors)
C) Diabetes secondary to Endocrinopathies
i) Cushings Disease
ii) Glucocorticoid administration
iii) Acromegaly
D) Diabetes secondary to immune suppression
E) Diabetes associated with genetic syndromes
Prader willi syndrome
F) Diabetes associated with Drug therapy
IV) Type 4 DM Gestational diabetes mellitus (GDM)

5. Symptoms Of DM
Classical Triad
Polyuria - ↑urination
Polydipsia - ↑thirst & fluid intake
Polyphagia - ↑appetite
↑BSL→incomplete reabsorption in prox. Renal tubuli→ Glycosuria
→↑ osmotic pressure of urine →↓reabsorption of water →polyuria
→↑Fluid loss → Dehydration →↑thirst
Blurred vision – Glucose absorption →changes in shape of lenses
Diabetic ketoacidosis- Kaussmaul breathing, polyuria, nausea,
vomitting & Abdominal pain, altered state of
consciousness, coma, death
Glucose →Sorbitol(glucitol) by aldose reductase cause tissue
damage leads to retino neuro nephropathy

6. DIAGNOSIS
Normal GT Impaired GT DM
Fasting plasma
glucose (mg/dl)
< 110 110 -125 > 126
2hrs after glucose
load 75g (mg/dl)
< 140 > 140-199 >200
HbA1c <5.7% 5.7-6.4% > 6.5%
HbA1c – Glycosylated Hb/glycated Hb/glycoHb
In DM Good glycemic control 6.5-7% HbA1c
Reflects avg. BSL over preceding 90 to 120 days
Used to monitor T/t in DM
Sr. fructosamine- Glycemic control preceding 1-2 wks

7. Type 1 DM Type 2 DM
Age at onset Childhood/puberty Over age 35 yrs
Nutritional status at
time of onset
Undernourished Obesity present
Prevalence 10-20% 80-90%
Genetic
predisposition
Moderate Very strong
Defect Beta cells destroyed
eliminating insulin
production
Inadequate insulin
production,
Insulin resistance
Ketoacidosis Frequent Absent
Anti islet cell
antibody
>80% <5%

8. PATHOPHYSIOLOGY OF TYPE 1 DM
A) AUTOIMMUNITY-
Condition where ones own immune system attack
structure in one’s own body
Circulating antibodies against b-cells and insulin
Cytoplasmic & membrane bound Ag IAAS GAD HSP etc
Insulitis
Both humoral & cell-mediated immunity are stimulated
triggered by reaction to infection
B) GENETIC FACTORS
Ethnic differences, Familial clustering, High concordance
rate in twins 25-50%
HLA on Chromosome 6-
HLADR3/HLADR4

9. C) ENVIRONMENTAL INFLUENCE
Viruses-Coxaschie B, Mumps, Rubella, Reoviruses
Nutrition & dietary factors-
Cow’s milk protein
Contaminated sea food
Chemicals destroying beta cells – 1)Vacor 2) streptozotocin
Pancreatitis, trauma, tumours
Vit D in I yr of life
Faulty nerves in pancreas-

10. HONEYMOON PERIOD
Due to b-cell reserve optimal function & initiation of insulin
therapy.
Leads to normal blood glucose level without exogenous insulin.
Observed in 50-60% of newly diagnosed patients & it can last up to
one year but it always ends.

11. MANAGEMENT OF TYPE 1 DM
Education
Diet and meal planning
Insulin therapy
Monitoring
Educate child & care givers about:
 Diabetes
 Insulin
 Life-saving skills
 Recognition of Hypoglycemia & DKA
 Meal plan
 Sick-day management

12. Diet and Meal planning
Susrate and Charaka- 2,500 years ago
John Rollo -eighteenth century
Frederick Allen -modern history of the diabetic diet
Regular meal plans with calorie exchange options are
encouraged.
50-60% of required energy to be obtained from complex
carbohydrates.
Distribute carbohydrate load evenly during the day preferably
6 small meals with avoidance of simple sugars.
Encouraged low salt, low saturated fats and high fiber diet.

13. INSULIN
HISTORY
1500 BC Sushruta – ayurveda Diabetes First Described
In Writing that flies and ants were attracted to urine of
people with a mysterious disease that caused intense
thirst, enormous urine output, and wasting away of the
body-
250 BC Apollonius of Memphis coined the name
"diabetes” meaning "to go through" or siphon. Latin
word for honey is mellitus
150 BC Aretaeus the Cappadocian - melting down of
the flesh and limbs into urine

14. Early Diabetes Treatments
1000- Greek physicians recommended
horseback riding to reduce excess urination
1800s- bleeding, blistering, and doping were
common
1915- Sir William Osler recommended
opium
Overfeeding - compensate for loss of fluids
and weight
Early 1900s Dr. Frederick Allen,
recommended a starvation diet

15. Early Research
1798- John Rollo - excess sugar in the blood and urine
1813-Claude Bernard linked diabetes to glycogen
metabolism
1869- Paul Langerhans- a German medical student,
discovered islet cells in the pancreas
1889-Joseph von Mehring and Oskar Minkowski created
diabetes in dogs by removing the pancreas
1910-Sharpey-Shafer of Edinburgh suggested a single
chemical was missing from the pancreas. He proposed
calling this chemical "insulin."

16. Pancreas Extractors
1908- a young internist in Berlin, Georg Ludwig
Zuelzer created a pancreas extract named acomatrol.
Try in dying diabetic patient
1911 - E. L. Scott was partially successful in
extracting insulin with alcohol
1916-1920 - R. C. Paulesco, made an extract from the
pancreas that lowered the blood glucose of dogs.
Before insulin was discovered in 1921, everyone
with type 1 diabetes died within weeks to years
of its onset

17. 1921 BANTING & BEST
Frederick Banting & Charles Best – ligate pancreatic
duct extract islets with alcohol and acid-↓BSL in dog
Leonard Thompson- age14-year wt 64 lb injected
their extract - blood glucose to fall from 520 to 120
mg/dL in 24 hours
Leonard lived a relatively healthy
life for 13 years before dying
of pneumonia (no Rx then) at 27
Macleod & J B Collip – stable extract

18. Nobel Prize
 1921 – Banting & Macleod nobel prize for
physiology /medicine 1923
 1930- Hagedorm – protamine
 1950- T.Scott & Fisher – added zinc
 1955- Sanger- primary struct Nobel prize in
Chemistry 1958
 1959- Hodgkin- Tirtiary struct (1964)
 1977-Yalow and Berson- Radioimmunoassay for
insulin- Nobel prize in Medicine
 1983- Frank and Chance -Insulin gene cloned-
Recombinant DNA Insulin
 1988- Long acting insulin analogues

19. Structure & Chemistry
Pancreas – Islets 2% of Pancreas
Cells %islets Hormone Function
1 A(α) 20% Glucagon Hyperglycemic
2 B(β) 75% Insulin C-peptide
Amylin
Amylin- modulate appetite
Gastric emptying
3 D (δ) 3-5% Somatostatin Inhibitor of secretory cells
4 F-PP
G
<2% Pancr polypept
gastrin
Facilitate digestion
Insulin- polypeptide mol wt-6000,
2 aa chains A(21aa) & B(30aa)
Linked by disulphide bridge

20. Structure & Chemistry…..
Species Antigenicity A -Chain B-Chain
8th aa 10th aa 30th aa
Human Least Threonine Isoleucine Threonine
Pork Negligible Threonine Isoleucine Alanine
Beef High Alanine Valine Alanine
Human Insulin – Human sequence insulin as primary structure
identical to human insulin, chemical conversion of porcine insulin,
- Synthesis by E.coli & Yeast cultures
Insulin - Water soluble
Zn bring crystallization
Prolong action-Zn & Protamine

21. Biosynthesis & Storage of Insulin
 Human pancrea contain ~8mg insulin (200U) (1mg=28U)
 Biosynthesis involves- Transcription from insulin gene,
mRNA stabilization, mRNA Translation, Post translational
modifications
Preproinsulin(110aa)
peptidase
Proinsulin + peptide(24aa)
Ca dependant enzyme PC2 PC3
Carboxypeptidase E
Insulin + C-peptide(35aa)
Granules store in crystal form
2 Zn + 6 Insulin mol

22. INSULIN RELEASE

23. DEGRADATION OF INSULIN
Insulin→ Endogenous Exogenous (s.c.)
Liver clears 60% 30-40%
Kidney clears 35-40% 60%
Half life: 3-5 min
Basal insulin value: 5-15μU/ml
Meals peak value: 60-90 μU/ml

24. REGULATION OF INSULIN SECRETION
B) HORMONAL :-
Hormones like Growth Hormone,
Corticosteroids, Thyroxin
modify insulin release
PG E inhibit it
Intraislet paracrine interaction
B cell
insulin
A cell
glucagon
D cell
Somatostatin
+
+
-
-
-
A)CHEMICAL :- Glucose sensing mechanism- glucose entry in
beta cell & phosphorylation (glukokinase) – insulin release
Other – Amino acids, Fatty acid & Ketone bodies
Glucose induce 1st phase within 2 min f/b 2nd phase
sustained

25. C) NEURAL :-
Islet- Sympathetic & Vagal n.
1) α-2 stimulation-↓ insulin release (inhibition adenylyl cyclase)
2) β-2 stimulation-↑ insulin release (stimulate adenylyl cyclase)
3) Cholinergic muscarinic activation - Ach/vagal stimulation →
insulin release (IP3/DAG)→↑Ca intracellular
Primary central site – Hypothalamus
Stimulation of Ventrolat nu (feeding c) →↑ insulin release
Stimulation of Ventromed nu (satiety c) →↓ insulin release

26. Glucose Transporters (GLUT)
Transpor
ter
Tissue Glucose
(mmol/L)
Functions
GLUT 1 All tissue specilly
red cells & brain
1-2 Basal uptake of glucose
transport across BBB
GLUT 2 Β-cells of pancrea
Liver Kidney gut
15-20 Regulation of insulin rele-
-ase, glucose homeostasis
GLUT 3 Brain, Kidney,
Placenta & other
<1 Uptake into Neurons &
other tissue
GLUT 4 Muscle Addipose 5 Insulin mediated uptake
GLUT 5 Gut & Kidney 1-2 Absorption of Fructose

27. INSULIN RECEPTORS
Beta subunit has tyrosin kinase
Insulin bind to α subunit
High specificity & affinity

28. MECHANISM OF ACTION
Insulin + Receptor
(α subunit)
↓
Tyrosine kinase (β
subunit)
↓
Activate IRS
↓
Activation of Phosphatidyl inositol 3 kinase pathway & MAP
(mitogen activated protein) pathway
↓
Translocation of GLUT to cell membrane

30. Translocation of GLUT-glucose uptake
Insulin activate transcription facton – enhance DNA
synthesis, cell growth and division
Stimulate Na+ -K+ ATPase increase pump activity -
K+ accumalation

31. PHARMACOLOGICAL ACTIONS OF INSULIN
LIVER ADDIPOSE SKEL MUSCLE
CHO CHO CHO
1.↑Glycogen synthesis 1.↑Glucose uptake 1.↑Glucose uptake
2.↓Glycogenolysis 2. Inhibt flow of
gluconeogenic
precursor to liver
(Glycerol)
2.↑Glycogen synth
3.↓Gluconeogenesis 3.Inhibt flow gluconeo -
genic precursor to liver
(Lactate pyruvate)4.↑hepatic Glu uptake
Fat Fat Fat
1.↑Lipogenesis 1.↓Lipolysis 1. ↓Lipolysis
2.↓Ketogenesis 2.↑Trigly formation
Protein Protein Protein
1.↓Protein breakdown --------- 1.↑Protein synthesis
2.↑Protein synthesis --------- 2.↓Protein breakdown

32. Inhibit phosphorylase (-glycogenolysis)
Inhibit Phosphoenolpyruvate carboxykinase (-
gluconeogenesis)
More conc
Increase glycolysis (+glucokinase)
Glycogenesis (+glycogen synthase)

33. CLASSIFICATION OF INSULIN
Type Appea-
-rance
Action in hrs
Onset Peak Duration
RAPID ACTING
1.Insulin Lispro Clear 0.25 0.5-1.5 2-5
2.Insulin Aspart Clear 0.25 0.5-0.8 3-5
3.Insulin Glulisine Clear -- 0.5-1.5 1-2.5
4.Regular soluble Insulin Clear 0.5-0.7 2-4 5-8
INTERMEDIATE ACTING
1.NPH(Neut protamine hagedorn) Cloudy 1-2 8-10 12-20
2.Lente (IZS) Cloudy 1-2 8-10 12-20
LONG ACTING
1.Prota Zn Insulin Cloudy 4-6 14-20 24-36
2.Insulin Glargine Clear 2-5 5-12 18-24
3.Ultralente Cloudy 4-6 16-18 20-36
4.Insulin Detemir Clear 1-4 20-24
5.Insulin Degludec clear 2-5 24-40

35. CONVENTIONAL PREPARATIONS
Pork & Beef , Antigenic , Low cost
1) Regular (soluble) Insulin- stabilizes by Zn, form Hexamers
Inj. just before meal early pp hyperglycemia & late pp
hypoglycemia so inject 0.5 to 1 hr before meal
2) Lente Insulin- Insulin Zn Suspension two types in 7:3 ratio
Ultralente- Extended IZS Semilente- Prompt IZS
Crystalline Amorphus
Large particle Small particle
Long acting Short acting
3) Isophane-(NPH) Neutral protamine hagedorn
4) Protamine Zn Insulin(PZI)-

36. NEWER INSULINS
ANTIGENICITY OF INSULIN
Electrophoresis –
A- high mol wt contaminant
B- Proinsulin & intermediate product of proinsulin
C- Insulin Monomers
Antigenicity – A&B Component – eliminate →purified C insulin
Animal insulin production – need large no. of animals
DNA Technology research – identical to human insulin

37. 1) Enzymatic Modified Pathway – EMP
Enzymatic conversion of porcine to human insulin
Alanine replaced by Threonine
Crude insulin
↓ Transpeptidation
Threonine ester
↓ Trypsin organic solvent
Human insulin ester
↓
Gel filtration at low PH (remove trypsin)
↓
Anion exchange chromatography (remove unconverted porcine insulin)
↓
Cleavage & human insulin ester
↓
Chromatography (human insulin ester)
↓
Human monocomponent insulin

38. 2) CHAIN RECOMBINANT BACTERIA- CRB
Organism of known fermentation – insert synthetic gene
sequence of DNA for derived protein- by plasmid
Culture this organism-synthesized protein harvested by lysing
bacteria –purified & chemical conversion E.coli
3) PROINSULIN RECOMBINANT BACTERIA-
Pronsulin gene inserted same way – proinsulin chains cleaved
by carboxypeptidase E – human insulin & C-peptide- purified

39. Features Highly purified Conventional
1 Species Porcine Bovine/Porcine
2 Purification Chromatography Recrystallization
3 Purity Proinsulin fold Proinsulin & other pr
4 Immunogenicity Less More
5 PH of soluble
insulin
Neutral Acidic (2.5-3.5)
6 Mixibility Possible Not possible
7 Compatibility Compatible Less Compatible

40. CHARACTERISTICS OF NEWER INSULIN
Absorbed faster, Gap between sc inj & food shorter
Duration & onset of action –shorter-fasting hypoglycemia-so
inj given post dinner
More pure more effective
Neutral PH-more stable mixing & less painfull
Potency – more on wt basis
Less Antigenic
Not cause Lipodystrophy
Now cost is low
Disadvantage:-
Hypoglycemic unawareness

41. INDICATIONS OF NEWER INSULINS
1. Newly diagnosed DM pt
2. Pt t/t intermittently with insulin – surgery infection etc
3. Immunological insulin resistance
4. Allergic or local reaction to animal insulin
5. Pt developed insulin induced lipodystrophy
6. Pt develop insulin resistance to conventional
preparations
7. Rapidly progressive microagiopathy
8. During pregnancy

42. NEWER INSULINS
1) Purified porcine
i) Short – Actrapid
ii) Intermediate – Lentard (Lente), Insultard (NPH)
iii) Premixed – Mixtard (30/70)
2) Human Insulin
i) Short – Actrapid
ii) Intermediate – Monotard (Lente), Insultard (NPH)
iii) Long – Ultratard (Ultralente)
iv) Premixed – Mixtard (30/70)
3) Penfills
i) Short – Actrapid HM
ii) Intermediate – Insultard HM
iii) Premixed – Mixtard 10HM, 20HM, 40HM, 50HM

44. Route and absorption
Site: Abdomen arm buttock thigh
SC blood flow increase with massage hot bath
exercise
SC all insulin
Only regular can be give i.v.
Inhalational insulin (Afrezza) Technosphere insulin
Exubera discontinued –lung cancer and fibrosis
CSII insulin Pump-
Oral insulin- Liposomal encapsulated expensive
experimental

45. NEWER INSULIN ANALOGUE
SHORT ACTING:-
1) INSULIN ASP B10-
-Substituting aspartic acid for histidine at B10
-mitogenic experimentally
2) INSULIN LISPRO-
First genetically engineered – clinical use, slightly greater
reduction of HbA1c compared to regular insulin
3) INSULIN ASPART – as lispro
4) INSULIN GLULISINE- as lispro
CSII
5) Biphasic Insulin Aspart- 70:30 mixture isophane complex of
insulin aspart with uncomplexed. So intermediate action and
given twice daily before major meal

46. LONG ACTING –
1) NOVOSOL BASAL –
Contains Arginine, Glycine Threonine
Low bioavailability, so high doses req
2) INSULIN GLARGINE –
Peakless effect given OD
Fasting & interdigestive BSL ↓ irrespective of time of day
PH-4 Not mixable , Not control mealtime glycemia
Lower night time hypoglycemia
3) INSULIN DETEMIR – Fatty Acid acetylated insulin
Less hypoglycemia
4) Insulin Degludec: ultra long acting
flat plasma glucose lowering, for basal insulin requirement
less nocturnal hypoglycemia than insulin glargine

47. ADVERSE REACTIONS
1) HYPOGLYCEMIA-
Most common, Occurs in any diabetic -
Inadvertent inj of large doses, Missing meal,
Vigourous exercise
Counter regulatory sympathetic regulation- sweating
anxiety palpitation tremor
Neuroglycopenic symptoms – dizziness, headache, visual
dist, hunger, fatigue, weakness, muscular
incoordination, ↓BP Hypoglycemic unawareness
When BSL <40 mg/dl- mental confusion, abnormal
behaviour, seizure coma & death
Irreversible neurological deficit
Treatment:- Glucose oral, iv
Glucagon 0.5-1mg iv/ Adr 0.2 mg sc

48. 2) INSULIN ALLERGY & RESISTANCE
Conventional insulin – contaminating protein
IgE mediated , hypersensitivity
Urticaria, angioedema & anaphylaxis
3) LIPOATROPHY & LIPOHYPERTROPHY-
Lipoatrophy- immune response to insulin
Lipohypertrophy- enlarge subcut fat-→ lipogenic action
of high local conc. Insulin
T/t- To change site of inj regularly
purified human insulin
4) INSULIN EDEMA-
Dependant edema – sodium retention

49. DRUG INTERACTIONS
1) Beta blocker inhibit compensatory mechanism - prolong
hypoglycemia, mask warning signs , ↑BP
2) Thiazide, Furosemide, corticosteroid, Salbutamol, OC -
↑BSL
3) Alcohol ppt hypoglycemia – depleting hepatic glycogen
4) Salicylate Lithium, Theophylline – hypoglycemia
accentuate

50. USES OF INSULIN
1) DIABETES MELLITUS-
Type 1 DOC
Purpose-
Restore metabolism to normal
Prevent death & alleviate symptoms
Prevent acute & chronic complications
Achieve biochemical control

51. Type 2 DM controlled by diet & exercise
need insulin when
Not controlled by diet & exercise
OHA prim/sec failure or not tolerated
Under wt pt
Any DM complication
Temporary tide over infection, Trauma, Surgery,
Pregnancy, Perioperative monitoring
Regular insulin- sc before meal
Requirement – assess by BSL & Urine sugar
Type 1 – 0.4-0.8 U/kg/day
Type 2- 0.2-1.6 U/kg/day

52. Regimens-
1) Typical split mixed regimen- reg/lispro/aspart &
intemediate acting (NPH/Lente) twice daily before
breakfast & dinner
2) In above evening dose of NPH/Lente is delayed at
bed time
3) Long acting insulin Glargine OD for basal coverage
& rapid acting at meal time

53. 4) Premeal short acting & Long acting NPH/Lente at breakfast &
bed time
Goal- Fasting BSL – 90-120 mg/dl
PP - < 150 mg/dl, HbA1c < 7% / <6.5%
Less disciplined- Fasting-140 mg/dl, PP- 200-250 mg/dl

55. 2) DIABETIC KETOACIDOSIS
Infection (mc) Trauma, stroke, Pancreatitis, Stressful conditions

56. Treatment-
1) Insulin- regular insulin, 0.1-0.2 U/kg iv bolus f/b 0.1 U/kg/hr
infusion, fall in BSL 10% per hr adequate
when BSL 300mg/dl – 2-3U/hr , after full conscious sc therapy
2) IV Fluids- correct dehydration
NS 1L/hr, ↓ 0.5L/4hr depend on dehydration,
Stabilize pt (BP HR) ½ NS
when BSL 300mg/dl 5% Glucose in ½ NS –
i. BSL ↓ before ketones cleared
ii. For restore depleted hepatic glycogen
3) KCl- 400 meq K+ lost, intracellular store replace, after insulin K+
driven intracellularly →Hypokalemia
After 4hr 10-20meq/hr add to iv fluid
4) Sodium Bicarbonate- 50 meq till PH>7.2
5) Phosphate – 5-10 meq/hr
6) Antibiotics & other support T/t of ppt cause

57. 3) Hyperosmolar (Nonketotic Hyperglycemic) Coma -
Type 2 DM
Dehydration, Glycosuria → diuresis, hemoconc.→↓
urine output→↑BSL >600mg/dl→↑plasma osmolarity
>320mOsm/L → coma, death
T/t – like ketoacidosis, Faster fluid replacement req, less
insulin and K+ requirement, no NaHCO3 req
prone to thrombosis- prophylactic heparin
4) Hyperkalaemia: insulin causes entry of K+ in cells so
given along with glucose
5) Miscellaneous: Historical- i) to test completeness of
vagotomy
ii) insulin shock therapy in schizophrenia

58. Somogyi Phenomenon Dawn Phenomenon
1. Type 1DM & Pt on insulin 1. Normal person or DM pt
2. Morning hyperglycaemia due to
increase level of hormones that tend to
increase glucose level in response to
nocturnal hypoglycaemia (Hypothesis).
2. Early morning hyperglycaemia –
Requirement if insulin increased in
the morning so in DM there may be
early morning hyperglycaemia and in
normal requirement fulfilled.
3. Solutions
a) Decrease night time dose of insulin
in type 1 DM (as not proved that
nocturnal hypoglycaemia is
responsible for Morning
hyperglycaemia ) so not suitable
b) There may be decrease response of
intermediate acting insulin – so
increase dose of it before bed time or
at bed time
c) CSSI- Basal rate of release may be
increased between 3-7 am
3. If hyperglycaemia throughout night
is not controlled then evening dose
divided - premeal evening dose of
regular insulin f/b (NPH) isophane
insulin at bed time.

59. Pathogenesis of DM type 2
The disease is influenced by genetic factors, aging,
obesity, and peripheral insulin resistance rather than
by autoimmune processes or viruses..
Beta cell dysfunction
• Decreased Sensitivity to stimuli
• Decreased number
The long-term clinical consequences can be just as
devastating (for example, vascular complications and
subsequent infection can lead to amputation of the
lower limbs)

60. Insulin Resistance
Insulin resistance refers to suboptimal
response of body tissues, especially liver,
skeletal muscle and fat to physiological
amounts of insulin.
Advanced age, obesity and sedentary life-style
promote insulin resistance.
When insulin requirement is increased
(Conventionally >200U but physiologically
>100 U)

61. 1) Acute Insulin resistance -
(a) Infection, trauma, surgery, emotional stress
induce release of corticosteroids and other
hyperglycaemic hormones which oppose
insulin action.
(b) Ketoacidosis—ketone bodies and FFA inhibit
glucose uptake by brain and muscle.
Treatment is to overcome the precipitating cause
and to give high doses of regular insulin till
normal condition achieved.

62. 2) Chronic Insulin resistance:-
Pt treated for years with conventional insulin
and antibodies produced to homologous
proteins are also bind to insulin. Common in
type 2 DM
Switch over to more purified insulin (Beef-
pork –human) decrease requirement over wk
months to stabilise pt at 60 U/day
Conditions for Insulin resistance:- Pregnancy
and oral contraceptives acromegaly, Cushing’s
syndrome, pheochromocytoma, HT

63. ORAL HYPOGLYCAEMIC /ANTIDIABETIC DRUGS
CLASSIFICATION
A) Enhance Insulin secretion
1. Sulfonylureas (KATP Channel blockers):
First generation: Tolbutamide Chlorpropamide
Second generation: Glibenclamide (Glyburide),
Glipizide, Gliclazide, Glimepiride
2. Meglitinide/phenylalanine analogue:
Repaglinide, Nateglinide
3. Glucagon-like peptide-1 (GLP-1) receptor agonists
(Injectable drugs): Exenatide, Lixisenatide,
Liraglutide, Dulaglutide, Albiglutide

64. 4. Dipeptidyl peptidase-4 (DPP-4) inhibitors: Sitagliptin,
Vildagliptin, Saxagliptin, Teneligliptin, Gemigliptin,
Linagliptin, Alogliptin
B. Overcome Insulin resistance
1. Biguanide (AMPK activator): Metformin
2. Thiazolidinediones (PPARγ activator):Pioglitazone
C. Miscellaneous antidiabetic drugs
1. α-Glucosidase inhibitors:Acarbose, Miglitol, Voglibose
2. Amylin analogue: Pramlintide
3. Dopamine-D2 receptor agonist: Bromocriptin
4. Sodium-glucose cotransport-2 (SGLT-2) inhibitor:
Dapagliflozin, Canagliflozin, Empagliflozin

65. Sulfonylureas (KATP Channel blockers)
All have similar pharmacological profile - lowers
blood glucose in normal person and Type 2 diabetics
Only 2nd generation drugs are used now – except
Tolbutamide
Glyburide- max insulotropic and sequestered within
B cells, also not safe in renal failure
Mechanism of Action
In the β cells - block the SU receptor (SUR 1) of
pancreas (a subunit of inwardly rectifying ATP-
sensitive K+ channel (KATP )

66. Insulin released at any glucose concentration
(even at low conc.) – severe and unpredictable
hypoglycaemia risk
Mainly the 2nd phase of insulin release
Presence of at least 30% β cells is must for
their action (no action on pancreatectomized
subjects and Type 1 diabetics)
A minor action reducing glucagon secretion-
by increasing insulin and somatostatin release
Hepatic degradation of insulin - slowed.

67. Extrapancreatic action:
- Action wears off after a few months – down
regulation of SUR1 receptors – but
improvement in glucose tolerance maintained
- Sensitize target tissues (liver) to insulin action
– due to increase in insulin receptors
- long-term improvement in carbohydrate
tolerance lower circulating insulin conc. which
reverses the down regulation of insulin
receptors (increase no.)
- Inhibits gluconeogenesis
- Antioxidant action-Glimepiride, Gliclazide

68. Pharmacokinetics: A) Well absorbed orally
D)highly (90%) bound to plasma proteins – low Vd
M) Metabolized in liver and/or kidney to active /
inactive E) Urine
Drug Interactions
Drugs that enhance SU action (ppt hypoglycaemia)
(a) Displace from protein binding: Phenylbutazone,
sulfinpyrazone, salicylates, sulfonamides.
(b) Inhibit metabolism: Cimetidine ketoconazole, sulfonamides,
warfarin, chloramphenicol
(c) Prolongs action (synergism): Salicylates,Propranolol
Drugs decrease SU action (vitiate diabetes control)
(a) Induce metabolism: Phenobarbitone, phenytoin, rifampicin,
chronic alcoholism.
(b) Opposite action/suppress insulin release: Corticosteroids,
thiazides, furosemide, oc.

69. Adverse effects of SU
1) Hypoglycaemia: Commonest (elderly, liver and
kidney diseases)
2) Nonspecific s/e: Nausea, vomiting, flatulence,
diarrhoea – Weight gain
3) Hypersensitivity: Rash, photosensitivity, purpura,
flushing and disulfiram-like reaction
4) Chlorpropamide: dilutional hyponatraemia (by
sensitizing kidney to ADH action), cholestatic
jaundice and alcohol flush.
5) Tolbutamide: Decrease iodine uptake by thyroid but
no hypothyroidism
6) Pregnancy and Lactation: safety not established
change to insulin Secreted in milk

70. Meglitinide/phenyalanine analogues
1) Repaglinide: Binds to SUR – closing of channel –
depolarization – Insulin release
–Rapidly metabolized, fast onset and short lasting action
–Administered just before meals - control of
postprandial hyperglycaemia
S/E:- Hypoglycaemia: Lower risk , do not skip meal,
less allergic and less wt gain than SU
Headache dyspepsia arthralgia
–Uses: Type 2 DM with severe postprandial
hyperglycaemia as supplementary to metformin;
Avoided in Liver diseases
•

71. 2) Nateglinide: D-phenylalanine derivative - `
stimulates 1st phase of insulin secretion –
closure of β cell KATP Channel
–Shorter lasting and faster onset – less risk of
hypoglycaemia than Repaglinide
–Less frequent hypoglycaemia
– Used in Type 2 DM with others antidiabetics
–ADRs: Nausea, Flu like symptoms and joint
pain

72. Glucagon-like peptide –1 receptor agonists –
injection preparations
•GLP – 1 is an Incretin – Oral glucose release
1) induces insulin release
2) inhibits glucagon release
3) slows gastric emptying,
4) suppresses appetite via GLP – receptors (GPCR) – in
α and β cells, GIT mucosa, central neurons
5) Incretins promote β cells health – decrease apoptosis,
its dysfunction in Type 2 DM
glucosedependent Insulinotropic peptide (GIP) - insulin
release but poor action in type 2 DM

73. GLP-1 not used clinically – rapid degradation by
Dipeptidyl peptidase – (DPP-4) enzyme – in luminal
membrane of capillary endothelial cells, kidney, liver,
gut mucosa
1) Exenatide: Synthetic DDP-4 resistant analogue of
GLP-1 – similar action with GLP-1
–Ineffective orally – given SC, half life 3 hours (6-10
hours duration)
– used in Type 2 DM along with others (Metformin);
- ADRs: Nausea and vomiting
- Benefits: Lowers body weight, postprandial and
fasting glucose and HbA1c

74. 2) Liraglutide: Similar to Exenatide
- ineffective orally – given SC
- longer duration of action ( >24 hours) – only
once daily dosing; safe in renal failure
- Benefit – weight loss (approved for obesity)
3) Albiglutide and Dulaglutide: very long acting
Once week inj
4) Lixisenatide: OD

75. Dipeptidyl peptidase – 4 (DPP-4) inhibitors
MOA: Prevents rapid degradation of GLP-1 by DPP-4
so it’s action prolonged
– orally effective adjunctive drugs – indirectly acting
insulin secretagogue
Sitagliptin: Competitive and selective DPP-4 inhibitor
Potentiates action of GLP-1 and increases insulin
secretion and inhibits glucagon, improves β cell
health, body weight neutral, well tolerated
– No effects of gastric emptying and appetite and no
hypoglycaemia
– Lowers HbA1c (equivalent to metformin)

76. Uses: As adjunctive drug if not controlled by
Metformin /SU/Pioglitazone , Monotherapy
only if metformin cannot be used
– PKinetics: Orally absorbed, metabolized little,
excreted unchanged in urine– half life – 12 hours
– ADRs: Nausea, loose stool, headache rash – cough &
nasopharyngitis (Substance P)
Vildagliptin: Binds to DPP-4 covalently – complex
dissociates slowly
P/K: Short plasma half-life 2 – 3 hours, but duration of
action 12 – 24 hours; Metabolized in liver Dose
reduction in liver and kidney diseases
Less selective DPP-4 than Sitagliptin and hepatotoxicity

77. Saxagliptin: Like vildagliptin, it binds
covalently with DPP-4 and acts for 24 hours
plasma t½ of 2–4 hr
It is metabolized by CYP3A4 and active
metabolite has t½ of 3–7 hours. DI with
CYP3A4 inhibitors
Teneligliptin: long DPP4 inhibition >24hrs
Single morning dose – postprandial
hyperglycaemia suppress for all 3 meals
Excretion by liver & kidney, no dose reduction
req in renal impairment

79. Biguanides (AMPK activator):
Metformin
No hypoglycaemia in normal, even in diabetics less
episodes. No β cell stimulation
Improve Lipid profile in type 2 DM ↑HDL and ↓LDL
VLDL
PK: half-life 1 – 3 hours and 6- 8 hours duration of
action not metabolised excretion by Kidney
Clearance appx to gfr

80. Mechanism of action Metformin
AMP dependent protein kinase (AMPK) activation
1. Suppresses hepatic gluconeogenesis and glucose
output from liver
2. Overcome insulin resistance in Type 2: enhance
insulin-mediated glucose uptake and disposal in
Muscles and Fats – more glycogen storage, reduce
lipogenesis and enhanced fatty acid oxidation.
Enhance GLUT 1
3. Promotes peripheral glucose utilization through
anaerobic glycolysis – interfere mitochondrial chain
4. Retards absorption of glucose, other a.a. and vit B12
5. Promotion of insulin binding to receptor

82. ADR
1) Abdominal pain, anorexia, nausea, metallic taste,
tiredness
2) Lactic acidosis: ↓glucose absorption so
↑availability of glucose for conversion to lactate.
Less LA by metformin, alcohol can ppt
3) Vit. B12 deficiency: interfere absorption
megaloblastic anemia
Contraindications: hypotensive states, heart failure,
severe respiratory, hepatic and renal disease,
alcoholics - increased lactic acidosis.

83. Use: First choice drug in all Type 2 DM, if
tolerated. Anorexia and wt loss : Obese pt
Advantages: nonhypoglycaemic, weight loss promoting
has potential to prevent macrovascular as well as
microvascular complications of diabetes
no acceleration of β cell exhaustion in type 2 DM.
antihyperglycaemic efficacy (HbA1c reduction by 0.8–
1.2%) equivalent to other oral drugs.
Can be combined with any other antidiabetic
PCOD: Improve ovulation and fertility in some women
with polycystic ovary (PCOD) as it ↓ insulin resistance
and level

84. Thiazolidinedione (PPARγ agonist)
Pioglitazone
MOA:
1) act as agonists of a nuclear receptor ; peroxisome
proliferator activated receptor gamma (PPARγ)
mainly in Fat cells, also in muscle and other cells. It
regulates the transcription of genes involved in
glucose and lipid metabolism. –Adiponectin, Fatty
acid transport protein, Insulin receptor substrate,
GLUT 4. reverse insulin resistance in type 2 DM
2) Enhances GLUT4 expression and translocation so
increase uptake and utilization of glucose
3) Suppression of hepatic gluconeogenesis

85. MOA glitazones…….
4) Activation of genes regulating fatty acid metabolism
and lipogenesis in adipose tissue – insulin sensitizing
action. fatty tissue major site of action.
- accelerated adipocyte turn over and differentiation.
- Lipolysis and plasma fatty acid levels are reduced.
5) ↓ HbA1c level
6) ↑HDL ↓TG little effect on LDL Rosiglitazone ↑LDL
USE: Type 2 DM with insulin resistance and
combination with SU/Met.
potential to prevent type 2 DM in prediabetes
Metabolism by CYP3A4,CYP2C8 , OC failure
Ketoconazole inhibit metabolism

86. ADR
1. Weight gain
2. Edema-fluid retention
3. Increase in fracture risk in women
4. Mild Anemia- plasma vol expansion hemodilution
5. Headache myalgia
6. Pioglitazone is associated with increased risk of
bladder cancer on long term use
7. Rosiglitazone Banned (2010)increases the risk of
angina , MI, CHF, Stroke and death.
8. Troglitazone was withdrawn due to serious
hepatotoxicity so LFT advised with others
CI: CHF Liver diseases, children pregnancy lactation

89. Saroglitazar (PPAR Agonist)
Dual PPAR agonist (peroxisome proliferator
activated receptor )
Higher activity for PPAR α(↓blood Lipid) Than
PPARγ(↓blood glucose)
↑HDL, ↓TG, ↓ LDL, ↓ blood glucose and↓HbA1c
Insulin sensitizer
Use: 1)Diabetic dyslipidemia and
2) Hypertriglyceridemia with type2 DM not
controlled by statin alone

90. α Glucosidase inhibitors - Acarbose,
Miglitol, Voglibose
MOA: (1) Inhibits α-glucosidase enzyme – brush
border of small intestine - decreases absorption of
poolysaccharides (starch etc.) and sucrose. also inhibit
α- Amylase (2) Release GLP-1

91. Reduces postprandial hyperglycaemia – no
significant increase in insulin level
Reduces HbA1c level - but less effect on weight
and lipid levels
Restoring β-cell function and prevent new cases of
type 2 diabetes in pre-diabetics.
Reduce cardiovascular events in type 2 DM
ADR: Flatulence: due to fermentation of unabsorbed
carbohydrates. abdominal discomfort, loose
stool(so C/I in IBD) poor pt compliance

92. Given with SU if Hypoglycemia occur- t/t
with glu not sucrose Miglitol more potent
sucrase inhibitor
C/I- 1) IBD
2) Miglitol absorbed from git and excreted
in urine 2/3 so C/I in renal failure
Use: Adjuvant to diet in obese type 2 DM before
meal. (decrease blood glucose in both type 1 as
well as type 2 diabetes)

93. Amylin analogue Pramlintide
Pramlintide is a synthetic analog of islet
amyloid polypeptide (IAPP) also called amylin
Action: 1) Decrease glucagon secretion
2) Delay gastric emptying 3) Decrease appetite
Route: SC
Can cause Weight loss and hypoglycemia
Use : Approved for treatment of type 2 as well
as type 1 diabetes mellitus

94. Sodium glucose co-transporter-2 [SGLT-2]
Inhibitors: Dapagliflozin and canagliflozin
MOA: Glucose filtered at the glomerulus is reabsorbed
in the proximal tubules by Sodium glucose co-
transporter-2 [SGLT-2]. SGLT2 Inhibitors reduce
renal reabsorption of glucose (Glycosuria), so reduce
the blood sugar

95. Advantages:
1) Wt loss, Oral route
2) No hypoglycemia: excess glucose excreted and not
induce insulin secretion
3) Improve insulin resistance as ↓toxic BSL
4) Diuresis: beneficial for DM with HT
5) Empagliflozin ↓ risk of CVS mortality
Disadvantages:
1) Efficacy reduced in renal failure
2) increased incidence of urinary tract infections and
genital infections.
3) Higher rates of breast and bladder cancers - dapaglif
4) ↓BMD ↑risk of bone fracture,Polyuria, polydipsia,
Na loss.

97. Dopamine D2 agonist
Bromocriptine
FDA has approved (2009) bromocriptine
mesylate as an adjunct to diet and exercise to
improve glycemic control in type -2 diabetes.
Early morning dose- act on the hypothalamic
dopaminergic control of the circadian rhythm
of hormone (GH, prolactin, ACTH, etc.)
release and reset it to reduce insulin resistance.

98. bile acid binding resins
Colesevelam is used for type 2 DM.
• The mechanism of action involves:
– An interruption of the enterohepatic circulation
(decrease in hepatic glucose output)
– A decrease in farnesoid X receptor (FXR) activation.
• FXR is a nuclear receptor with multiple effects on
cholesterol, glucose, and bile acid metabolism.
• The drug may also impair glucose absorption.
Side effects – constipation, dyspepsia, abdominal pain,
and nausea

99. Epalrestat
Inhibitor of aldose reductase and inhibit
formation of sorbitol in nerves and other tissue
so delays Diabetic neuropathy
Improves nerve conduction and neuropathic
pain
Other Drugs as adjuvant to diet:
Guargum: diatary fibre reduce cholesterol and
CHO absorption
Glucomannan: tubers of konjar extract swell in
stomach reduce appetite BSL Lipid

100. Status of Oral antidiabetics
Contraversy
UGDP study of USA (1970):cardiovascular mortality
was higher in patients treated with biguanides and
SUs than in those treated with diet and exercise alone
or with insulin.
Settled by UK PDS trial: 1) SUs and metformin did
not increase cardiovascular mortality
2) insulin and SUs reduced microvascular complications
3) Metformin reduce macrovascular complications also,
decreased risk of death in overweight patients.
4) Thiazolidinedione and metformin ↓ insulin resistance

101. Oral hypoglycemics are indicated only in type 2
diabetes, in addition to diet and exercise.
They are most effective in patients with—
• Age above 40 years at onset of disease.
• Obesity at the time of presentation.
• Duration of DM < 5 yr when starting treatment.
• Fasting blood sugar < 200 mg/dl.
• Insulin requirement < 40 U/day.
• No ketoacidosis or a history of it, or any other
complication.

102. Prediabetes impair GT: delay in progression by
metformin, Glitazones and acarbose type
Oral hypoglycaemics- supplement dietary
management and not to replace it.
Metformin- obese type 2 DM- Anorectic ↓wt
↓risk of MI and Stroke poor GI tolerance less
pt acceptability
SU- SUs are the most commonly selected 2nd
drug. good patient acceptability, convenient
dosing and high efficacy, but can cause weight
gain and hypoglycaemia .
Second generation SUs preferred more potent
less S/E & Drug interactions.

103. SU may fail primary 5-28% or secondary 5-
10% per yr 1) progressive loss of B cell 2) less
physical activity 3) insulin resistance continue
4) drug & dietary noncompliance 5) SUR
Desensitisation
SU+Metformin any ineffective alone
Post-prandial hyperglycaemia, or late postmeal
hypoglycaemia - repaglinide/nateglinide
Pioglitazone is usually the 3rd choice drug;
may be added to metformin or a combination
of metformin + SU. Due to ADR
Acarbose- supplementary but disliked by pt

104. DPP 4 inhibitors: second line/add on
antidiabetic drugs.
- Valuable for patients more body weight and
frequent episodes of hypoglycaemia
- supress glucagon release-decrease fasting BSL
also
- improve beta cell health so retard progression
- body wt neutral
- can be used in renal impairment
- Single dose no drug interaction well tolerated

105. - Mod HbA1c lowering
- Some serious ADR angioedema anaphylaxis
reported
- Impact on CVS mortality and other yet to
established
Upto 50% patients of type 2 DM initially
treated with oral hypoglycaemics ultimately
need insulin.
Moreover, when a diabetic on oral
hypoglycaemics presents with infection, severe
trauma, surgery or stress, pregnancy, any
complication switchover to insulin

108. ICMR Guideline
2018

110. recent
Intravenous Glyburide
• As a treatment for acute stroke, traumatic brain injury
and spinal cord injury
• Based on the identification of a non-selective
ATPgated cation channel which is upregulated in
neurovascular tissue during these conditions and
closed by sulfonylurea agents
Resveratrol – • Natural compound found in grape skin
• Improves insulin action, increases insulin stimulated
glucose uptake • Activation of gene Sirtuin-1
Glucokinase Activators – • Glucokinase – “Glucose
Sensors” • Mutations – Diabetes • PIRAGLIATIN
Salsalate – • NSAID • Reverses Insulin Resistance

111. Ref:
Goodman & Gilman's: The Pharmacological Basis of
Therapeutics
Essentials of Medical Pharmacology, KD Tripathi,
Edition, 8/e.
Principles of pharmacology: HL Sharma, KK Sharma
Pharmacology for MBBS by Dr. S.K. Srivastava
Therapies for diabetes by Bailey CJ
Basic & Clinical Pharmacology, Bertram G. Katzung.
Harrison's Principles of Internal Medicine
ICMR Guideline for Diabetes Mellitus
ADA guidelines
Various internet searches