This document presents information on complications, management, and treatment of diabetes mellitus. It defines diabetes as a group of metabolic diseases involving high blood glucose levels due to inadequate insulin production or cells not responding to insulin. It discusses the types and classifications of diabetes, epidemiology, clinical manifestations, acute and chronic complications, and current pharmacological and non-pharmacological treatment approaches including insulin, oral hypoglycemic agents, lifestyle changes, and education. The goal of diabetes management is to eliminate hyperglycemia symptoms, reduce complications, and allow patients to live as normal a lifestyle as possible.

1. Presented by: ANAS HARUNA INDABAWA
Submitted to: Associate Prof. Dr P.S.Gupta
Final Year Project Presentation
Department: Pharmacy
School: Sam Higginbottom University of Agriculture, Tech. & Sciences
(SHUATS)
Year: March 2017

2. COMPLICATIONS, MANAGEMENT AND
TREATMENT APPROACH OF DIABETES
MELLITUS

3. Definition
• The Pancreas secretes insulin and
Glucagon directly into the blood
stream.
• It also secretes digestive enzymes
into the pancreatic duct, which
joins the common bile duct from
the liver and drains into the small
intestine.
• Insulin and Glucagon have
opposite effects on liver and other
tissues for controlling blood-
glucose levels.
Diabetes describes a group of metabolic diseases in which the person has
high blood glucose (blood sugar), either because insulin production is inadequate, or
because the body's cells do not respond properly to insulin, or both. Mellitus is Latin
for “sweet as honey”.
Pancreas is an elongated, tapered gland that is located behind the stomach
and secretes digestive enzymes and the hormones insulin and glucagon.

4. Glucagon (α alpha cells)
• Glucagon is produced in the α cells
and is released when the glucose
level in the blood is low.
• The liver then convert stored
glycogen into glucose and release it
into the bloodstream.
Insulin (β Beta cells)
• Beta Cells within the Islets of
Langerhans produce insulin which is
needed to metabolize glucose within
the body.
• Insulin is secreted in response to
increased glucose levels in the blood.

5. Epidemiology
• According to International Diabetic Federation (IDF) atlas
(2015), Governments have acknowledged that diabetes is
increasing at epidemic rates and is affecting all countries.
• Globally, an estimated 422 million adults were living with
diabetes in 2014, compared to 108 million in 1980 which is
estimated to be 1 in 11 of the world’s adult population.
• About 46% of people with diabetes are undiagnosed
• About 10% people with diabetes have Type 1 DM
• About 90% people with diabetes have Type 2 DM

6. Classification
• Type 1 diabetes
• Type 2 diabetes
• Other
1. Genetic defects of beta cell
function
2. Genetic defects in insulin
action
3. Diseases of the exocrine
pancreas
4. Endocrinopathies
5. Drug/ chemical - induced
6. Infections
7. Uncommon forms of
immune-mediated diabetes
8. Genetic syndromes
sometimes associated with
diabetes
• Gestational diabetes mellitus

7. Type 1
• Formerly known as Insulin –
Dependent Diabetes Mellitus
(IDDM)
• Type I diabetes occurs when the β-
cell are destroyed by the body’s own
immune system.
• May occur at any age, usually appears
below age 15.
• Usually due to autoimmune
destruction of the pancreatic beta
cells or idiopathic.
• Patients with type 1 diabetes will
need to take insulin injections for the
rest of their life.

8. Type 2
• Formerly known as Non Insulin –
Dependent Diabetes Mellitus
(NIDDM)
• Insulin is produced however there
is less and there is a decrease in
the number of receptors (insulin
resistance).
• occurs over age 40 but can occur
in children
Gestational DM
• Gestational diabetes (GDM)
occurs when pancreatic function
is not sufficient to overcome the
insulin resistance created by
changes in diabetogenic hormones
during pregnancy.
• Most have impaired glucose
tolerance that begins in pregnancy
• Some have previous undiagnosed
type 2 diabetes mellitus
• 10% have circulating islet cell
antibodies

10. Etiology
• There is no defined cause of diabetes
because the causes of diabetes vary
depending on the individual and the
type.
• Some of the risk factors include:
– Obesity (BMI >25 kg/m2)
– History of CVD
– Diet
– Physical inactivity
– Familial history
– Increase in age
– Smoking
– Race/ethnicity (e.g., African
American, Latino, Native
American, Asian American,
Pacific Islander)
– Viral infection
– Gestational Diabetes

11. Clinical Manifestations ( Signs and
Symptoms)
• Polyuria
• Polydipsia
• Polyphagia
• glycosuria
• weight loss
• weakness
• nausea / vomiting
• fatigue
•  blood sugar
• recurrent infection
• prolonged wound healing
• altered immune and inflammatory
response, prone to infection. (glucose
inhibits the phagocytic action of
WBC  resistance)

12. Complications
 I. Acute complications:
 diabetic ketoacidosis
 hypoglycemia
 diabetic nonketotic
hyperosmolar coma
 Lactic acidosis
 II. Chronic complications:
a. Microvascular
 retinopathy
 nephropathy
 neuropathy
 diabetic foot
 dermopathy
b. Macrovascular
 Cerbrovascular.
 Cardiovascular.
 peripheral vascular
disease.

13. Diabetic complications cont…
Diabetic ketoacidosis
• Diabetic Ketoacidosis (DKA) is a
state of inadequate insulin levels
resulting in high blood sugar and
accumulation of organic acids and
ketones in the blood.
• It is a potentially life-threatening
complication in patients with
diabetes mellitus.
• It happens predominantly in type
1 diabetes mellitus, but it can also
occur in type 2 diabetes mellitus
under certain circumstances.
• It may also be the first
presentation in patients who had
not previously been diagnosed as
diabetics.
• There is often a particular
underlying problem that has led to
the DKA episode.
• This may be intercurrent illness
(pneumonia, influenza,
gastroenteritis, a urinary tract
infection), pregnancy,
inadequate insulin
administration (e.g. defective
insulin pen device), myocardial
infarction (heart attack), stroke
or the use of cocaine.
• This is more common in African,
African-American and Hispanic
people.

14. Diabetic complications cont…
• The ketone bodies, however, have
a low pH and therefore turn the
blood acidic (metabolic acidosis).
• The body initially buffers this with
the bicarbonate buffering system,
but this is quickly overwhelmed
and other mechanisms to
compensate for the acidosis, such
as hyperventilation to lower the
blood carbon dioxide levels.
• This hyperventilation, in its
extreme form, may be observed
as Kussmaul respiration.

15. Diabetic complications cont…
Diabetic Hyperglycemic
Hyperosmolar State (HHS)
Relative insulin deficiency and
inadequate fluid intake are the
underlying causes of HHS.
• Insulin deficiency increases hepatic
glucose production (through
glycogenolysis and gluconeogenesis)
and impairs glucose utilization in
skeletal muscle .
• Hyperglycemia induces an osmotic
diuresis that leads to intravascular
volume depletion, which is
exacerbated by inadequate fluid
replacement.
• HHS is often precipitated by a
serious, concurrent illness such as
myocardial infarction or stroke.

16. Diabetic complications cont…
Lactic Acidosis
•Lactic acidosis occurs in hypoxic
individuals and is due to an excessive
production of lactate by peripheral
tissues.
•It is characterized by extreme
metabolic acidosis.
•There is high anion gap with low or
absent ketones and high lactate
levels.
Hypoglycemia
• Hypoglycaemia is caused by not
eating enough sugary foods,
taking too much insulin therapy or
too much exercise.
• Low blood glucose can lead to
coma.

17. Diabetic complications cont…
Diabetic Retinopathy
• Diabetes causes an excessive
amount of glucose to remain in
the blood stream which may
cause damage to the blood
vessels.
• Within the eye, the damaged
vessels may leak blood and fluid
into the surrounding tissues and
cause vision problems.

18. Diabetic complications cont…
Other Eye Complications
Cataracts.
Glaucoma
Macular edema.
Ischaemic maculopathy.
Proliferative retinopathy.
Vitreous Bleeding.
Rubeosis Iridis

19. Diabetic complications cont…
Diabetic nephropathy
• Diabetic nephropathy
(nephropatia diabetica), also
known as Kimmelstiel-Wilson
syndrome, and intercapillary
glomerulonephritis, is a
progressive kidney disease.
• The kidney becomes damaged
and more protein than normal
collects in the urine. Over time,
the kidney's ability to function
starts to decline, which may
eventually lead to chronic kidney
failure.

20. Diabetic complications cont…
Diabetic Neuropathy
• Diabetes can damage the nerves.
This generally begins as loss of
sensation in the toes, and possibly
fingers.
•It may manifest as polyneuropathy,
mononeuropathy, and/or autonomic
neuropathy.
• Both myelinated and unmyelinated
nerve fibers are lost.

21. Diabetic complications cont…
Diabetic Foot
• Diabetic foot ulceration is due to
an interplay of neuropathy, tissue
ischaemia (microcirculatory and
macrovascular disease) and
secondary infection.
• The factors responsible for its
development, in addition to
peripheral vascular disease, are
small vessel disease, peripheral
neuropathy with loss of both pain
sensation and neurogenic
inflammatory responses, and
secondary infection.
The peripheral sensory neuropathy
interferes with normal protective
mechanisms and allows the patient to
sustain major or repeated minor
trauma to the foot, often without
knowledge of the injury.

22. Diabetic complications cont…
Macrovascular complications
• Accelerated atherosclerosis
involving the aorta and large- and
medium-sized arteries.
• Myocardial infarction, caused
by atherosclerosis of the coronary
arteries, is the most common
cause of death in diabetics.
• Gangrene of the lower
extremities.
• Hypertension due to Hyaline
arteriolosclerosis.

23. Management of Diabetes Mellitus
The goals of therapy for type 1 or type 2 DM are to:
(1) Eliminate symptoms related to hyperglycemia,
(2) Reduce or eliminate the long-term micro vascular and macro vascular
complications of DM, and
(3) Allow the patient to achieve as normal a lifestyle as possible.

24. Current therapy of DM
• Non-Pharmacological
• TYPE 1 Management (Insulins)
• TYPE 2 Management (Oral
Hypoglycemic Agents)

25. Non-Pharmacological Therapy of DM
• Weight Loss
• Regular Physical activity
• Medical Nutrition Therapy
• Lifestyle Changes
• Education

26. PHARMACOLOGICAL
TREATMENT FOR DIABETES
Agents used in diabetic therapy include the following:
• Biguanides
• Sulfonylureas
• Meglitinide derivatives
• Thiazolidinediones (TZDs)
• Alpha-glucosidase inhibitors
• Glucagonlike peptide–1 (GLP-1) agonists
• Dipeptidyl peptidase IV (DPP-4) Inhibitors
• Amylinomimetics
• Selective sodium-glucose transporter-2 (SGLT-2) inhibitors
• Bile acid sequestrants
• Insulin

27. Biguanides
• Metformin (Glucophage, Fortamet, Glumetzam, Riomet)
• Metformin inhibits hepatic and renal gluconeogenesis, and increases the
sensitivity of insulin receptors.
• It does not cause hypoglycemia.
• It produces a significant ↓ TG and LDL, and ↑HDL.
• There is a serious concern about lactic acidosis especially in patients with
kidney disease.
• Other preperations:
penformin
buformin
– Withdrawn due to high risk of lactic acidosis

28. Sulfonylureas
• First generation : Acetohexamide, Chlorpropamide, Tolbutamide, Tolazamide
• Second generation : Glipizide, Glyclazide, Glybenclamide – more potent,
more efficacious and fewer adverse effects.
• Third generation : Glimiperide
• Mechanism of Action Sulfonylureas act by Binding to sulfonylurea receptors
on pancreatic islet cells, closing KATP channels, stimulating insulin release;
relatively long duration of action
• Increases the beta-cell insulin secretion and may also decrease rate of hepatic
glucose production and increase insulin receptor sensitivity
Adverse effects :
• Hypoglycemia
• Cholestatic jaundice
• Weight gain
• Cross placenta – fetal hypoglycemia.
• Chlorpropamide : It can cause water retention by ↑ release of ADH (SIADH)

30. Meglitinide
Repaglinide, Nateglinide :
• More rapidly acting insulin enhancers and shorter duration than
sulfonylurea.
• Mechanism of Action: Meglitinide Bind to sulfonylurea receptors on
pancreatic islet cells, closing KATP channels, stimulating insulin release;
relatively short duration of action
• Hypoglycemia is the common adverse effect.
• Less weight gain
• The drug has minimal renal excretion thus useful in patients with DM and
impaired renal function.

31. Thiazolidinediones
Rosiglitazone, Pioglitazone
• Thiazolidinediones Activate the nuclear receptor PPAR-gamma, increasing
peripheral insulin sensitivity; also reduces hepatic glucose production
• Enhance sensitivity to insulin in muscle and fat by increasing the GLUT 4
glucose transporters.
• Beneficial effects on serum lipid; ↓TG and ↑HDL.
• Troglitazone is associated with hepatitis.
• Edema.

32. Alpha-Glucosidase Inhibitors
Acarbose , Miglitol,Voglibose
• It inhibits α-glucosidase which converts dietary starch and complex
carbohydrates into simple sugars
• It reduces absorption of glucose after meals.

33. Glucagon like Peptide: GLP-1 analog
Exernatide, Albiglutide, Lixisenatide, liraglutide
• GLP is an incretin released from the small intestine which increase the
glucose dependent insulin secretion.
• Exenatide suppress glucagon release and reduce appetite
• Glucagon like Peptide: GLP-1 analog Increase glucose-dependent insulin
secretion, decrease glucagon secretion, and delay gastric emptying; inhibit
degradation of endogenous GLP-1 (and GIP-1), thereby enhancing these
effects of these incretins

34. Dipeptidyl peptidase 4 (DPP-4)
Inhibitors
Sitagliptin, saxagliptin, Linagliptin, Vildagliptin
• It inhibit the dipeptidyl peptidase 4 (DPP-4), an enzyme which
inactivates the incretins GLP-1 and GIP, that are released in
response to a meal.
• It potentiates the secretion of insulin and suppress the release of
glucagon by the pancreas.

36. Amylinomimetics
Pramlintide
• Amylin: a polypeptide
produced by pancreatic
beta cells which reduces
glucagon secretion from
alpha cells and delays
gastric emptying
• It acts by stimulation of
glucagon receptors and
not through beta 1
receptors.
• It has positive inotropic
action and chronotropic
action on the heart.

37. SGLT2 Inhibitors
Dapagliflozin, Empagliflozin
• SGLT2 Inhibitors Reduces
glucose reabsorption in the
proximal renal tubules and
lowers the renal threshold for
glucose, thereby increasing
urinary glucose excretion.
• Possible challenge:
– Increase in incidence of
UTI
– Hypotension
– Bladder cancer,
amputations, fractures

38. Bile acid sequestrants
Bromocriptine (Cycloset)
• This quick- release formulation is the only bromocriptine product
indicated for type 2 diabetes mellitus. It is indicated as an adjunct to diet
and exercise to improve glycemic control.

39. Insulins
• Proinsulin is converted to insulin
and C peptide.
• Insulin is referred as the storage
hormone as it promotes anabolism
and inhibits catabolism of
carbohydrates, fatty acids and
protein.
• In the absence of insulin, most
tissues cannot use glucose and
fats/proteins are broken down to
provide energy.
Mechanism of action :
• Insulin binds to insulin receptors
on the plasma membrane and
activates tyrosine kinase –
primarily in adipose tissue, liver
and skeletal muscle.
• The Nerves, RBC’s, Kidney, and
Lens of the eye do not require
insulin for glucose transport.

40. Insulins
Methods of insulin administration
1) Insulin syringes and needles-
Plastic disposable syringes are
available in 1-mL, 0.5-mL, and
0.3-mL sizes.
2) Insulin pen injector devices-
Insulin pens eliminate the need for
carrying insulin vials and syringes.
3) Insulin pumps-Insulin infusion
pumps are used for subcutaneous
delivery of insulin. These pumps
are small (about the size of a pager)
and very easy to program.
4) Inhaled insulin-A novel method
for delivering a pre-prandial
powdered form of insulin by
inhalation (Exubera) has been
approved by the FDA.

41. Product (Manufacturer) Form
Rapid Acting (Onset 15-30 min, duration hrs 3-4)
Insulin Analog
Aspart - Novolog (Novo Nordisk)
Lispro - Humalog (Lilly)
Glulisine – Apidra (Aventis)
Analog**
Analog**
Short Acting (Onset 0.5-1 hr, duration hrs 5-7)*
Human Insulin
Novolin R (Rugular) (Novo Nordisk)
Humulin R (Regular) (Lilly)
Human**
Human**
Purified Insulin
Regular Iletin II (Lilly) Pork
Intermediate Acting (Onset 1-4 hrs, duration hrs 18-24)*
Human Insulin
Novolin N (NPH) (Lilly)
Humulin N (NPH) (Lilly)
Humulin L (Lente) (Lilly)
Human**
Human**
Human**
Purified Insulin
NPH Iletin III (Lilly) Pork
Long Acting (Onset 4-6 hrs, duration hrs 24-34)*
Human Insulin
Humulin Ultralente (Lilly) Human**
Basal Peakless Insulin
Glargine-Lantus (Aventis)
Detemir – Levemir (Novo Nordisk)
Analog**
Analog**
Product (Manufacturer) Form
Mixed Insulins
70/30 Insulin
Novolin 70/30 (Novo Nordisk)
Humulin 70/30 (Lilly)
Humulin 50/50 (Lilly)
Humalog 50/50
Human**
Human**
Human**
Analog**
Insulin for Special Use
Buffered Insulin (for pumps)
Humulin BR
Refills for Novolin Pen
Novolin R PenFill
Novolin N PenFill
Novolin 70/30 PenFill
Novolog Mix 70/30 PenFill
Prefilled Pens
Novolin R
Novolin N
Novolin 70/30
Novolog
Novolog Mix 70/30
Humalog
Humalog Mix 75/25
Humalog Mix 50/50
Humulin N
Apidra
Human**
Human**
Human**
Analog**
Human**
Human**
Human**
Analog**
Analog**
Analog**
Analog**
Analog**
Human**
Analog**
* Onset and duration are rough estimates. They can vary greatly within the range
listed and from person to person
** Human insulin is made by recombinant DNA technology

42. Newer Approach
• New potential targets of Carbohydrate Metabolism
– Glucokinase (GK) Activators
– Fructose-1,6-Bisphosphatase(FBP)Inhibitors
– GlycogenPhosphorylase(GP)Inhibitors
• New potential targets of lipid Metabolism
• Beta3-Adrenergic Receptor (β3-AR) Agonists
• Hormone Sensitive Lipase (HSL) Inhibitors
• GPR40 /(Free Fatty Acid Receptor 1 (FFAR1)) Ligands

43. New Potential
Targets of
Carbohydrate
Metabolism

44. Glucokinase (GK) Activators
• Enzymes of the
glycolytic pathway that
converts glucose to
glucose-6-phosphate
• Glucose sensor
• Upregulating insulin
(from pancreas)
• Promoting glucose
storage as glycogen
• Piragliatin - Phase 2
Possible concern –
• Increased hepatic
glycogen, lipid
deposition in liver and
muscle

45. Fructose-1,6-Bisphosphatase (FBP)
Inhibitors
• (FBP) is the
Gluconeogenesis
enzyme that
catalyzes the
reverse conversion
(F1,6P to F6P)
• FBPi - decrease
Hepatic Glucose
Production
• Efficacy has been
an issue
• Phase 2 - MB07803

46. Glycogen Phosphorylase (GP) Inhibitors
• Glycogenolysis is a
substantial contributor to
hyperglycemia
• GP produces glucose-1-
phosphate converted to
glucose-6-phosphate which
feeds into glycolysis
• GP(a) inhibition of the
liver isoform in a selective
fashion is important
• Ingliforib - phase 1

47. New potential
targets of lipid
Metabolism

48. Beta3-Adrenergic Receptor (β3-AR)
Agonists
• Activate the uncoupling protein (UCP) which causes the expenditure of
metabolic calories as heat
• Preclinical stages
• Lipolysis & β oxidation
• Low bioavailability
• Efficacy is less
• Is it suitable?? β3AR stimulated thermogenesis to expend excess energy in
human diabetic patients is still undefined

49. Hormone Sensitive Lipase (HSL)
Inhibitors
• Rate-limiting step in adipose tissue lipolysis
• FFA’s - inhibits glucose uptake and utilization by muscle, increasing HGP
• HSLi improved lipid profiles and elevated insulin sensitivity (reduced
plasma glucose levels)
• Preclinical stages

50. GPR40 /(Free Fatty Acid Receptor 1
(FFAR1)) Ligands
• FFAR1 facilitates glucose-stimulated insulin secretion from pancreatic β-
cells
• GPR 40 regulates the secretion of glucagon-like peptide-1 in the intestine,
as well as increases insulin sensitivity
• Potential therapeutic targets for type 2 DM
• Chronic exposure impairs β-cell function (lipotoxicity)
• Phase II : TAK-875

51. FUTURE PROSPECTS
• Islet cell transplantation is a
minimally invasive procedure,
wide application of this procedure
for the treatment of type 1
diabetes is limited by the
dependence on multiple donors
and the requirement for potent
long-term immunotherapy.
• Stem cell therapy- Stem cell
therapy is one of the most
promising treatments for the near
future. It is expected that this kind
of therapy can ameliorate or even
reverse some diseases.

52. THANK YOU