DIABETES MELLITUS

DEFINITION
 Diabetes mellitus(DM) is an endocrine
disorder, characterized by hyperglycemia due
to impaired insulin secretion with or without
insulin resistance.

 Diabetes is a chronic disease, which occurs

when the pancreas does not produce enough
insulin, or when the body cannot effectively
use the insulin it produces. This leads to an
increased concentration of glucose in the
blood (hyperglycaemia).
 Normal Blood Glucose levels
 Normal blood glucose(NBG) :55 - 140
mg/dL (<7.8mmol/L).
 Diabetes mellitus: ≥200 mg/dL (11.1
mmol/L).

 Normal Fasting plasma glucose

(FPG):<100 mg/dL (5.6 mmol/L).
 Diabetes mellitus : ≥126 mg/dL (7.0
mmol/L).
 Minimum Glucose for normal
function : 40-60 mg/dL.

 If the glucose level is above

180mg/dL kidney fails to reabsorb.
In diabetes Glucose may present in
urine also.
 CLASSIFICATION
Based on Aetiology

 TYPE I
• Insulin Dependant Diabetes Mellitus

 TYPE II
• Non Insulin Dependant Diabetes Mellitus

 OTHER SPECIFIC TYPES

 TYPE I : Insulin Dependant Diabetes Mellitus
(IDDM)
† ß cell destruction and absolute insulin
deficiency.
† 5-10% of total DM
† latent autoimmune diabetes in adults (LADA).

¤TYPE I A : Autoimmune T cell, Human leukocyte

antigen DR3 or DR4, virus, toxins mediated
destruction

¤TYPE I B : Idiopathic
 TYPE II : Non Insulin Dependant Diabetes
Mellitus(NIDDM)

‡ 90% of total DM

‡ Secretary defect with or without insulin resistance.

‡ Also called as “insulin resistance syndrome”

 Other specific types

 Gestational diabetes mellitus (GDM)

• Gestational diabetes is defined as glucose intolerance
that begins or is first detected during pregnancy.

 Genetic defects of β-cell function

 Genetic defects in insulin action
 Endocrinopathies
• Cushing’s syndrome
• Pheochromocytoma
• Hyperthyroidism
• Aldosteronoma
 Infections (viral)
• Cytomegalovirus

 Diseases of the exocrine pancreas

• Pancreatitis
 Drug- or chemical-induced
• Nicotinic acid
• Thiazides
• Phenytoin
 PATHOPHYSIOLOGY
 TYPE I : Immune mediated destruction of
pancreatic β cells or idiopathic process.

 Features : presence of immune markers.

hyperglycemia.
transient remission( honeymoon phase).

 Immune response normally by Macrophage, T lymphocyte,

autoantibody, islets antibodies.
 INSULIN
islets of Langerhans(1% of Pancreas)

β cells synthesizes Preproinsulin

Converted into Proinsulin

Insulin + C-peptide
 Insulin- A chain(21 amino acid)+B chain (30 amino
acid)
They connected with 2 disulfide bridges.
Insulin synthesis

6 11
7 10

19
7
 Release and actions of Insulin
 Stimulus (Glucose is main)
 Initial rapid response (2 minutes), the

stored insulin get released in to blood.

 Secondary response (5min-1hr), newly

synthesized insulin.

Basal state: 1 unit/hr

Stimulus : 5-10 fold
Total release per day : ≈40 units*
Half life of insulin : 4-5 min
*1 unit =0.01 mls of insulin
Release of Insulin
 ACTIONS OF INSULIN
 Increases uptake of glucose and its utilization.

 Increases uptake & conversion of glucose to its storage

form.

 Decrease hepatic glucose production & suppression of

glucagon.

 Muscle : Glucose → Glycogen.

 Adipose : Glucose → VLDL → storage in adipose tissue &
inhibit lipolysis.

 Insulin facilitates amino acid entry and their synthesis

into proteins.
 Type I : Insulin
deficiency
Glycogenolysis & Glucose uptake by
Gluconeogenesis tissue

Glucose output

Blood Glucose

Glucagon, Cortisol, Metabolic

Catecholamine, GH disturbance
 CLINICAL MANIFESTATION
 Polyuria and Polydipsia with Hyperglycemia.
 Blurred vision, Polyphagia (excessive hunger),
Sudden weight loss, Recurrent infections
 Glycosylated hemoglobin.

 TYPE I :
 Ketoacidosis
 Postural hypotension
 Dizziness
 Weakness
 Anorexia, nausea, vomitting.
 Rapid ventilatory rate (Kussmaul respiration)
 TYPE II :
 Phagocytes dysfunction due to
hyperglycemia.
 Skin infections
 Retinopathy, neuropathy, peripheral
vascular disease.
 DIAGNOSIS

 Symptomatic diagnosis: Polyuria,

polydipsia and weight loss, plasma
glucose concentration ≥11.1 mmol/L,
Urine tests(glucosuria, ketonuria), oral
glucose tolerance test.

 Non-symptomatic diagnosis: Random

glucose determination, glycated
haemoglobin(HbA), C-peptide assay,
 DIABETIC EMERGENCIES
 Hypoglycaemia: (≤ 3.5 mmol/L)
 may because of oral hypoglycemic (long acting
Sulfomnylureas) agents or insulin.
• Symptoms:
 Autonomic: sweating, tachycardia, palpitations,
adrenalin secretions, glucagon release.

 Neuroglycopenic : faintness, loss of

concentration, drowsiness, confusion, coma.

 Other: hunger, headache, numbness.

• Causes: carbohydrate, uptake by cells,
enhanced hypoglycemic effect, exercise,
liver diseases.

• NOCTURNAL HYPOGLYCEMIA:
Hypoglycemia at night time headache,
restlessness etc
 But at morning blood glucose will be higher because of
reflex mechanisms.
 Blood glucose should be measured at 2-3am.
• TREATMENT OF HYPOGLYCEMIA :
 Glucose (powder, tablet, drink, iv(20%)
 Glucagon (iv)
Diabetic Ketoacidosis
 Insulin ↓ → release of non-esterified fatty acids
→ metabolism of tricarboxilic acid causes the
release of ketone bodies(acetoacetic acid,
hydroxybutyrate)
↓
Diabetic Ketoacidosis(DKA)

 glucose in cell → cell starts oxidation of

stored lipid and produces acetyl CoA → this
reaction produces ketone bodies also →
Ketoacidosis.
• Osmotic dieresis less volume dizziness,
weakness, postural hypotension. K+ loss.
• Due ketoacidosis deep & rapid respiration
(Kussmaul respiration). with Fruity odour.

• Diagnosis: Urinalysis for glucose & ketones.

Blood glucose (>22mmol/L).

• Treatment: Fluid Supplement (0.9% NaCl).

Correction of hyperglycemia.
Prevention of hypokalaemia.
 Hyperosmolar nonketonic hyperglycemia:

 Hyperglycemia over a long period causes hyperosmolar

nonketonic hyperglycemia.

Diagnosis: Hyperglycemia (55.5mmol/L)

Confusion Coma
Seizures
Creatinine

Treatment: Fluid Supplement (0.9% or 0.45% NaCl).

Insulin
+/- K+ Supplement
 Long Term Diabetic Complications:

Cerebrovascular disease, abnormal ECG,

Hypertension, Absent of foot pulse, Retinopathy,
Nephropathy, Erectile Dysfunction.

 Macrovascular Disease:

Cardiovascular Disease: MI, Dyslipidimia, Cardiac

autonomic neuropathy, Hypertension.

Peripheral Vascular Disease: Cramping pain in legs ,

Reversible muscle ischemia, erectile dysfunction.
 Microvascular Disease:

Nephropathy: develop as a consequence of

structural abnormalities, including glomerular
basement membrane thickening (elevated glucose
concentrations increase collagen synthesis),
changes in glomerular epithelial cells (podocytes),
including a decrease in number and/or density,
glomerulosclerosis, and tubulointerstitial fibrosis.
Diabetic retinopathy:
 Diabetic retinopathy is a
complication of diabetes that results
from damage to the blood vessels of
the light-sensitive tissue at the back
of the eye (retina).
• Thickening of basement membrane.
• Capillary thrombi and get occluded.
• Bleeding
• Fibrovascular and gliotic tissue
contracts to cause retinal
 Peripheral neuropathy: loss of
sensation, weakness, wasting(thigh
muscle), impaired hands/foot co-
ordination, impaired bladder tone,
diarrhea, postural hypotension.
 Pathologic changes due to

hyperglycemia occurs to peripheral

neurons.
 Segmental demyelination, axonal

damages are common pathological

  Micro-Macro disease combined:
Foot ulcers

Neuropathic Ischemic ulcers Neuro-ischemic

Loss of pain due to Peripheral Vascular

nerve death/damage Disease
Blood supply
Pain less Ulcers
O2 & nutrients

No healing(Pain full)
 Management of Diabetes
 Diet :
• Carbohydrates which have lower glycemic index.
• Have regular meals based on starchy foods(bread,
potatoes, rice, cereals etc)
• Decrease saturated fat.
• Cut down sugar, sugary foods and alcohol.

• Proteins – 1g/Kg (if no nephropathy)

• Fiber – carbohydrate absorption

• ≈15 g of soluble fibers/day.

• Salt – NaCl  maximum of 6g/day.

 INSULIN TERAPY:

 Type I : exogenous insulin that mimic

normal physiological patterns of
insulin.

 Chronic type II diabetes.

 Duratio
Origin Onset Peak
Insulin n
(hr) (hr) (hr)
(hr)
Soluble Insulin
Human actrapid H 0.5 1-3 8
Bovine neutral B 0.5-1 2-5 6.8
Pork actrapid P 0.5-1 1-3 8
Biphasic Insulin
Human mixtard H 0.5 2-12 24
Pork mixtard P 0.25 4-8 24
Isophane Insulin
Hypurin porcine P 2 6-12 24
Human insulatard H 2 4-12 24
Insulin Zinc Suspension
Human monotard H 3 7-15 24
Hypurin bovine lente B 2 8-12 30
Long acting analogues
Lantus (insulin glargine) H 2-4 NO PEAK 20-24
Levemir (insulin detemir) H 2-4 6-14 16-20
Protamine Zinc
Hypurin Bovine PZI B 4 10-20 36
 Porcine insulin : from Pork. Differ
from human insulin at B30.
• Semi-synthetic human insulin may be
produced by enzymatic modification.

 Recombinant insulin : by using

recombinant DNA tech.
• Human proinsulin gene into Yeast or
E.coli.
 Insulin preparations :

 Fast-acting insulins : it is soluble insulin analogue

also called as neutral insulin. It is clear solution.
• Onset of action <10mins; duration of action is 2-4hr.
• Lower risk of hypoglycemia.
• Only Insulin monomers.

 Intermediate acting insulins : Insulins are insoluble,

cloudy suspensions of insulin complexed with either
protamine or zinc.
• Onset of action 1-2hr; duration of action is 8-12hr.
• Protamine insulin will not interact with soluble insulin so it can be
mixed with and admin.
• Zinc suspension will precipitate on mixing with soluble insulin, so
it should be administered immediately.
 Long-acting insulins : 24hr of action

 Insulin glargine: 2 arginin is added to the B chain.

A21 Asparagine is replaced by Glycine.
 Long action  production of microprecipitate &
slow release.

 Insulin detemir: omission of threonine at B30 and

attachment of a fatty acid chain (Myristic acid).

 ADRs of insulin: hypoglycemia,

lipohypertrophy, allergic reaction.
 Insulin delivery
 Insulin syringes
 Pen devices
 Jet injections
 Insulin pumps
 Implantable pumps
 External artificial pancreas
 Oral hypo glycemic Drugs
 Sulfonylureas: It binds to the Sulfonylurea
receptors, it is a ATP dependent K+  leading to
decreased potassium influx  depolarization of
the membrane.

 Voltage-dependent Ca+2 channels open  inward

flux of Ca+2Increases in intracellular Ca+2
exocytosis of the granule of insulin.

 Elevated secretion of insulin from the pancreas

travels via the portal vein and subsequently
suppresses hepatic glucose production.
 First-generation agents
• Tolbutamide – 250 mg
• Acetohexamide – 500 mg
• Tolazamide - 250 mg
• Chlorpropamide -500 mg
 Second-generation agents
• Glipizide – 5-50 mg/kg
• Glyburide – 5mg

 Side effects: hypoglycemia, leucopenia,

thrombocytopenia, skin reactions, diuresis,
anemia, nausea, headache, weight gain.
 Biguanides : They enhance peripheral
glucose uptake and inhibit glucose release
from liver.
They wont produce hypoglycemia when used
alone.

 Metformin : 0.5-1 gm.

 Phenformin : 50 mg.

 ADRs : GIT disturbances, weight loss, lactic

acidosis, cardiac risks, Vit B12 deficiency.
α glucosidase enzyme inhibitors:
It also inhibit glucoamylase and
sucrose enzymes.  decrease the
absorption rate of carbohydrates.

Miglitol(50-300mg thrice daily)

Acarbose(50-300mg thrice daily).

ADRs : abdominal discomfort, diarrhea.

 Short acting secretogogues : It having
same mechanism of action of Sulfonylureas. It
binds to the sulfonylurea receptor and
increases the insulin secretion.

 They are chemically Meglitinide

analogues.
 Rapaglinide : 0.5-2mg.
 Nateglinide : 120mg before meals.

 ADR: headache, weight gain, dyspepsia.

 PPARγ (Peroxisome proliferator-activated
receptor) agonists : It increases nuclear
transcription.

 Chemically they known as Thiazolidinediones

(glitazones)

 Peroxisome Proliferator-Activated Receptors

(PPARs) are a group of nuclear receptor proteins
that function as transcription factors regulating
the expression of genes.

Stimulates GLUT4 expression and translocation.

entry of glucose to cells is improved.
activation of genes regulating fatty acid metabolism.

 Rosiglitazone ,pioglitazone,troglitazone.
 DRUG INTRACTIONS

Drug Class Interacts with Result

Phenylbutazone,
Increases plasma
saicylates,
concentration
sulfonamides.

Sulfonylureas Allopurinol,
Decreases excretion
probencid.

Phenylbutazone, Decreases
chloramphenicol. metabolism

Biguanides Cimetidine Decreases excretion

 Special populations
 Elderly patients : Short acting insulin
secretagogues or low-dose-
sulfonylureas.

 Gestational DM : Glucose conc

should be 50-130mg/dL. NPH
(neutral protamine hagedorn) or
mixture of NPH with isophane (2:1)
before breakfast.
 References

 Clinical pharmacy and therapeutics

– ROGER WALKER; 4th edition; page
no:629-652.

 Pharmacotherapy – DIPIRO ; 6th

edition; page no: 1333-1363

 Text Book Of Therapeutics by

ERIC T HERFINDAL ; 6th edition.
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