Diabetes mellitus is a metabolic disorder characterized by hyperglycemia resulting from defects in insulin secretion or action. There are several types of diabetes including type 1 caused by beta cell destruction and type 2 caused by insulin resistance. Chronic complications of diabetes include microvascular complications like retinopathy, neuropathy, and nephropathy as well as macrovascular complications like cardiovascular disease. Treatment involves lifestyle changes, oral hypoglycemic agents like sulfonylureas and metformin, and insulin therapy. Strict glycemic control can help reduce the risk of complications.

1. Diabetes Mellitus
HARESH DESAI

2. DIABETES MELLITUS (DM)
 DM-a metabolic disorder with
hyperglycemia,glycosuria, hyperlipaemia, -ve
nitrogen balance & sometimes ketonaemia.
 Defects in insulin secretion, insulin action or both =
micro/macrovascular complications.
 Pathological change is thickening of capillary
basement mem; increase in vessel wall martix-leads
to narrowing of lumen, early
atherosclerosis,retinopathy & neuropathy.

3.  Acco. To international diabetic fedration-----------
1995—19million
 2007---40.9 million/double
 Projection: 69.9millions in 2025
 11% urban &3% rural population above the age of 15
have diabetes.
 India—the diabetes capital of the world.

5. normal diabetes
 Fasting-80-100mg/dl
 PP2 BS < 140mg/dl
 HbA1c -- < 7%
 > 126 mg/dl
 > 200mg/dl
Blood glucose level

6.  Classification of DM:
 Type 1
 Type 2
 Gestational diabetes
 Prediabetics
 Others– genetic defects, disease of pancreas, drug
induced, infections.

7. Type 1 (IDDM ) Type 2 (NIDDM)
 BETA cell destruction in
pancreatic islets;
 Majority of cases are
autoimmune (type 1A )
Antibodies that destroy beta
cells are detected in blood, but
some are idiopathic, ( type 1 B
)
 Occur in young
children(juvenile onset )
 Less common (10% )
 Low degree of genetic predisp.
 No loss or moderate
reduction in beta cell mass;
 Insulin is low, normal or
even high
 High degree of genetic
predisposition
 Late onset(past middle age
)
 90% cases
 Above 25 to 30 year
2 types

8.  Causes of type 2 DM could be :
 Abnormality in glucoreceptor of beta cells so that
they respond at higher glucose concentration or
relative β cell deficiency.
 Reduced sensitivity of periphe. tissues to insulin,
decrease in no of insulin receptors-down regulation of
insulin receptors.
 Excess of Glucagon, obesity.

9. Symptoms of DM
 Common symptoms
 Excessive thirst
(polydipsia)
 Excessive hunger
(polyphagia)
 Frequent urination
(polyuria)
 Weight loss
 fatigue
 Less common
 Cramps
 Constipation
 Blurred vision
 Candidiasis
 Skin infection

10.  Pancreas & Islets of Langerhans:
 Pancreas – located in C cells of the duodenum.
 In pancreas some cells are found in clusters (appear
like an island) , 1st described by a scientist –
Langerhans (18 feb in 1869 in his PHD thesis ).
 So called Islets of Langerhans

11.  Islets of Langerhans are made up of 4 different type
of cells----
 A—Alpha cells------------Glucagon
 B –Beta cells ------------Insulin
 C—Gamma cells--------pancreatic poly peptide
 D--- Delta cells---------Somatostatin

12.  Physiology of insulin :---
 Discovered by Banting & Best in 1921.(N P)
 1ST obtained in pure crystalline form in 1926 &
chemical structure was fully known in 1956 by
sanger.
 2 chain polypeptide—51 AA. /MW-6000.
 A –chain—21 AA
 B– chain—30 AA

13.  There are minor differences bet human, pork & beef
insulins.
 Pork= human.
 Insulin synthesized as a single chain peptide
preproinsulin(110AA)---24 AA 1st removed to form
proinsulin(inactive)
 When beta cells are stimulated by glucose
,proinsulin is degraded (c chain removed)& active
insulin (A& B ) are released in to the blood.

14.  The C peptide is secreted in the blood along with
insulin ( c peptide test is used to determine the
endogenous insulin reserve )

15. Release of insulin
 1 Glu binds with glu transporter prot.(GLUT)
 2 Glu enters in Beta-cells
 3 further metabolism of glu generates ATP
 4 This closes K+ channel so increase in intracellular K+
 5 Excess K+ depolarises Bcell& opens Ca++ channels.
 6 Ca enters in B cells
 7 Ca activates microtubules , that propels insulin
containing vesicles to cell surface
 8 EXOCYTOSIS

16.  Insulin release kinetics :-
 Total no of beta cells in a normal pancreas -10 to 20
crores– which can manufacture & release 40 to 50
units of insulin daily.
 Release as a single shot/15 min, means 4/hr or
96/24 hrs.
 93- are at a rate of 0.5 to 1unit/hr. for full 24 hrs.
(basal insulin ). It controls elevation of fasting BS
due to excess hepatic glucose output throughout the
whole day.

17.  The remaining 3 shots of insulin are produced
immediately after every major meal- which amounts
approx. 9-15 units depending on the individual
glucose load from each meal.
 In a normal healthy non- diabetics , there are 2
phases of insulin release-
 1- an early phase/1st phase that occurs within 1st 30
min. after glucose ingestion.
 2 – a later/2nd phase of insulin secretion.
 Once DM is established- both phases are lost.

18.  Actions of insulin producing hypoglycaemia-
 Liver- increases glucose uptake& glycogen synthesis.
Decreases glycogenolysis & gluconeogenesis.
 Muscle-increses glu uptake & utilisation,increases
glyco synthesis & deposition. Decreases proteolysis.
 Adipose tissue-increases glu uptake & storage,
decreases lipolysis & increases lipogenesis.

19.  Problems with insulin:-
 In 1920s – short acting, acid soln which causes pain
& impure insulins.
 1 – Hegedorn (1936) –in denmark- protamine
decreases insulin solubility. (NPH )
 2—Scott & fisher (1938 toronto)-addition of Zinc
+prota +insulin = action lasts for 3 days.(PZI)
 3 – Dr K Hallas Moller in Novo-insulin + zinc
prolonged action (in absence of prota).

20.  Conventional preparations of insulin :- from beef &
pork pancreas. (antigenic) ,now replaced by highly
purified pork/ recombinant human insulins/ insulin
analogues.
 Regular insulin – a buffered soln with zinc.
 Lente insulin(insulin –zinc suspension) 2 types
 1- long acting(crystalline , large particle)called ultra
lente or extended insulin zinc susp.
 2- short acting (amorphous ,smaller particle)called
semi lente or prompt insulin zinc susp.
 3- intermediate acting- called lente-insulin(with 3
parts of crysta.+ 7 parts of amorphous)

21.  Human insulins- (1980s)-
 Produced by recombinant DNA technology in E coli
– proinsulin recombinant bacterial(prb)
 In yeast – precursor yeast recombinant (pyr)
 By enzymatic modification of porcine insulin(emp)
e.g. Human actrapid.
 Human insu are more water soluble, hydrophobic,
more rapid s c abn & shorter duration of action.
 Uses- insulin resistance, allergy to conven; inj site
lipodystrophy, pregnancy.

22.  Insulin analogs – with recombinant DNA technology
– modified p.kinetics on s c inj. but similar p.
dynamic effects.
 Have greater stability & consistency.
 INSULIN LISPRO : produced by reversing proline&
lysine at B 28 & B 29.
 Rapid absorn.,act with in 15 min. after s c inj. Peak
60-90 min, duration 4-5 hours.

23.  INSULIN ASPART :-
 Proline at B -28 of human insulin is replaced by
Aspartic acid.
 This change reduces the tendency for self
aggregation.
 E.g. Novolog, Novorapid 100/ml.inj.

24.  INSULIN GLARGINE –
 Long acting.
 Has 2 additional arginine residues at the carboxy
terminus of B chain& glysine replaces aspargine at A-21.
 A depot is created (sc) from where insulin dissociates
slowly in the circulation.
 Onset is delayed but remains for 24 hrs. (OD)
 Does not control mealtime glycaemia. (rapid insulin,
OHA)
 E. g. lantus optiset 100u/mlin 5 ml vial.

25.  Insulin glulisine- rapidly acting insulin analogue
with lysine replacing aspargine at B 23 & glutamic
acid replacing lysine at B 29.
 Properties & advantages are similar to lispro.
 Used for continuous subcutaneous insulin infusion
by a pump.

26.  Adv effects of insulin :---
 1 Hypoglycaemia- commonest problem. (high dose,
missing meal, vigorous exercise )
 Treatment- glucose orally/iv , glucagon 0.5-1 mg iv or
adrenaline 0.2mg sc
 2 Swelling ,erythema& stinging.lipodystrophy at the
injection site (not with newer)
 3 Allergy-due to contaminated protein9rare with human)
 4 Oedema- (due to Na retention).

27.  Uses of insulin:-
 1 – DM:must for type-1
 2- Diabetes ketoacidosis- (diabetic coma)-most
common in type -1.
 Ppts cause= infection, trauma, stroke, pancreatitis,
stressful conditions.
 3- hyperosmolar nonketotic state (HNS)-common in
type-2.symptoms are same as ketoacidosis but
dehydration is there.

28.  Uncontrolled glycosuria of DM produces
diuresis=dehydration- urine output is finally reduced
& glucose accumulates in blood rapidly to 800mg/dl;
plasma osmolarity is > 350m osm/L ------leads to
coma & death .

29.  Treatment of diabetic ketoacidosis-
 1 –insulin-a bolus dose of 0.1-0.2U/kg is followed by
0.1U/kg/hr infusion.
 2-intravenous fluids –to correct dehydration.normal
saline ,rate of 1ltr /hr.
 3-KCL-as k+ is lost in ketoacidosis ,10 to 20meq /hr
KCL is needed to add in IV fluids.
 4-Phosphate- 5 to 10 mmol/hr of sodium/phosphate
infusion is advocated.
 5-Antibiotics.

30. Chronic complications
 Chronic complications-------------Vascular
Disease

31. Vascular Disease
 MICROVASCULAR AND MACROVASCULAR
 DIABETIC NEUROPATHY
 DIABETIC NEPHROPATHY
 DIABETIC RETINOPATHY
 DIABETIC CARDIOMIOPATHY
 DIABETIC ANGIOPATHY

32. Diabetic Neuropathy
 Abnormal and decreased sensation, usually in a 'glove and stocking'
distribution starting with the feet but potentially in other nerves, later often
fingers and hands. When combined with damaged blood vessels this can lead
to diabetic foot . Other forms of diabetic neuropathy may present as
mononeuritis or autonomic neuropathy. Diabetic amyotrophic is muscle
weakness due to neuropathy.

33. Diabetic Nephropathy
 Damage to the kidney which can lead to chronic renal failure,
eventually requiring dialysis. Diabetes mellitus is the most common
cause of adult kidney failure worldwide in the developed world.

34. Diabetic retinopathy
 Growth of friable and poor-quality new blood vessels in the retina as well
as macular edema (swelling of the macula), which can lead to severe vision
loss or blindness. Retinal damage (from microangiopathy) makes it the most
common cause of blindness among non-elderly adults in the US.

35. Diabetic cardiomyopathy
 Damage to the heart, leading to diastolic dysfunction and eventually
heart failure.

36. Diabetic Angiopathy
 Diabetic gangrene referred to as diabetic foot comes under peripheral
vascular diseases categorized under macro vascular diseases.

37. Oral hypoglycaemic agents(OHA)
 Insulin- X given orally.
 OHA- effective orally.
 In 1940- sulphonamides –hypogly. S/Es.
 1957- 1st clinically effective sulphonylurea is-
tolbutamide.
 In 1970- 2nd generation devoloped- 20 to 100 times
more potent.
 1957- biguanide phenformin .

38.  Classification:- 1 Sulfonylureas
 1st gen-tolbutamide,chlorpropamide
 2nd gen-glibenclamide, glipizide, gliclazide,
glimipride.
 2 Biguanides – phenformin, metformin
 3 Meglitinide/phenylalanine analogues-
repaglinide/nateglinide
 4 thiazolidinediones-pioglitazone,rosiglitazone
 5 α-glucosidase inhibitors-Acarbose, Miglitol

39.  Sulfonylureas :- all have similar pharmac action-
decreases blood glucose level in normal & in type 2
but not in type 1.
 MOA:- act on so called sulfonylurea receptors on the
pancreatic β cell mem. cause depolarisation by
reducing conductance of ATP sensitive K+ channels.
Thus causes increase in Ca influx= degranulation.
 Thus it provokes a brisk release of insulin secretion
from pancreas.

40.  They increases 2nd phase of insulin secretion , little
effects on phase 1.
 Do not cause hypogly in pancreatectomised animals
& in type 1 diabetics. (+ce of atleast 30% functional β
cells is essential for their action).
 A minor action- decreases glucagon.
 A hepatic degradation of insulin-slowed.
 Increase in insulin receptor No &affinity to insulin.

41.  Pharmacokinetics--
 Well absorbed orally
 90% bound to PP
 Excreted in urine.

42.  Adv effects –
 1 hypoglycaemia- commonest problem.more
common in elderly.
 Lower incidence with 2nd generation.
 2 non specific s/es- N/V , flatulence, diarrhoea or
constipation, headache, paresthesias
 WEIGHT GAIN.
 3 Hypersensitivity reactions- rashes,
photosensitivity, purpura, leucopaenia.
 Pregnancy –not safe,secreted in milk.

43.  Biguanides :- phenformin X due to lactic acidosis
(banned in india since 2003)
 Differ from 1st group= little or no hypoglycaemia in
nondiabetic subjects.
 Do not stimulate β cells.
 Metformin is reported to improve lipid profile in type
2 diabetics.

44.  MOA :-Do not cause insulin release but +nce of some
insulin is essential for their action.
 Explanations are- 1 supress hepatic gluconeogenesis
& glucose output from liver:the major action.
 2 increases insulin mediated glucose disposal in
muscle & fat.
 3 decreases intes abn of glu, other hexoses, AAs &
vitamin B12.
 4 reduces appetite- helpful in OBESE –patients.

45.  Adverse effects – abdominal pain, nausea,
ANOREXIA, METALLIC TASTE ,mild diarrhoea &
tiredness are frequent.
 Hypoglycaemia is rare except in overdose.
 Lactic acidosis – small increase in blood lactate but
lac acido is rare ( 1 in 10000 patients). Alcohol can
ppts it.
 Vit B12 deficiency –(interference with abn.)

46.  Meglitinide analogues – recently devoloped quick & short
acting insulin releasers.
 Repaglinide – a meglitinide analogue OHA
devoloped for normalise meal time glucose level.
 Not a sulfonylurea , but acts on it, produces insulin
release.(rapid onset/short lasting insulin release)-
control PP2BS.
 S/Es- WT.GAIN.
 uses: - alter to sulfo/supplement to metfo/LA
insulin.

47.  D phenyl alanine derivative-
 Nateglinide-stimulates 1st phase insulin secretion =
rapid onset & shorter action than repaglinide.
 Ingested 10-20min before meal, controls PP
hypergly. in type 2 without producing late phase
hypoglycaemia.
 S/Es – dizziness, nausea, joint pain, flulike
symptoms.

48. Thiazolidinediones
 Rosiglitazone-X
 Pioglitazone:-selective agonists for Nuclear Peroxisome
proliferator activated receptor –y(PPAR-Y ) which
increases the transcription of several insulin
responsive genes.
 They tend to reverse insulin resistance by stimulating
GLUT 4 expression & translocation : entry of glucose
in to muscle is improved.
 Hepatic gluconeogenesis- Suppressed.
 Improved glycaemic control = decrease in circulating
HBA1C & insulin levels in type 2.DM.
 Lowers TG & increases HDL (PPAR-α )

49.  Adverse effects :- plasma volume expansion, edema,
WT. GAIN, headache, myalgia, mild anemia.
 Few cases of liver dysfunction , & CV events .CHF
may be worsened.
 May decreases DM in prediabetics.
 Pioglitazone is also banned in india due to many
cases of bladder cancer.

50.  α-glucosidase inhibitors:-
 Acarbose- a complex oligosaccharide which reversibly
inhibits α-glucosidase ,the final enzymes for diges. of
carbo. In the brush border of small int. mucosa.
 Regular use of it lowers HbA1C, BODY WT, &serum
TG.
 Adjuvant to diet in obese patients.
 S/Es-flatulence, abd.discomfort & loose stools (50%)
due to fermentation of unabsorbed carbohydrates.

51. Newer approches in DM
 Incretin mimetics :-incretin is a group of hormones
which includes –GLP-1(glucagon like peptide-
1)&GIP-(glucose dependent insulinotropic
polypeptide), that are released after meals from
upper & lower bowel & augment glu. dependent
insulin secretion.
 GLP 1 is difficult to use , due to rapid degradation by
enz.dipeptidyl peptidase-4(DPP-4)
 EXENATIDE:-A synthetic GLP-1 analogue, resistant
to DPP-4, but with similar actions.(increase in PP
insulin release ,decrease in glucagon,appetite.)

52.  SITAGLIPTIN:- DPP-4 is a enz which inactivates
GLP-1.
 It is a DPP-4 inhibitor , orally active, prevents
degradation of GLP-1 , potentiates their action.
 It increases insulin secretion, decreases glucagon,
delays gastric emptying & suppresses appetite.
 S/Es: - nasopharingitis (subs p-substrate for DPP-4
whose levels get increased )
 Sitagliptin 100mg od/vildagliptin 50mg od before
meals.

53. Sita-gliptin

54. Amylin mimetic drugs
 Amylin is a neuroendocrine peptide hormone
cosecreted with insulin from beta cells.its role is to---
inhibit glucagon secretion, delays gastric emptying,
suppress appetite.
 Pramlintide:-a synthetic amylin analogue decreases
PP hyperglycemia (S C ), injected before meal & has
central anorectic action.

55.  Sodium Glucose Cotransporter -2 (SGLT-2 )
inhibitors—are dapaglifozin, serglifozin &
remoglifozin –(newer –phase 111 trials)
 The kidney continuously filters glucose through
glomerulus & nearly all of this glucose is reabsorbed
back from proximal tubule by a transporter – SGLT -
2.
 Inhibition of this= no reabn . = excretion.

56. MCQs
1-)The major route for Insulin administration is
a) Transdermal
b) Intradermal
c) Subcutaneous
d) Intramuscular
2-) Human /Highly purified insulin preparation is
indicated in the following situation
a) Allergic to conventional preparation
b) Pregnancy
c) Lipodystrophy
d) In above all situations

57. 3-) All of the following are short acting insulin
analogues except-
a) Insulin lispro
b) Insulin aspart
c) Insulin glulisine
d) Insulin glargine

58.  4-) Insulin action include the following except
a) Facilitates glucose transport into cells
b) Stimulates glycogenesis by liver and muscle
c) Stimulates lipolysis in adipose tissue
d) Increases the conversion of glucose to fatty acid

59. THANK
YOU