Diabetes mellitus

• Diabetes, is considered of great importance to the

health of the world, and is now taking its place as
one of the main threats in the 21st century.

• T2Diabetes mellitus (DM) is a group of metabolic

disease characterized by hyperglycaemia resulting
from defects in insulin secretion, insulin action or
both.
 Types of diabetes;
• Type 1 diabetes: type 1 diabetes most commonly afflicts
children, adolescents, or young adults, but some latent
forms occur later in life.
 Type 2 diabetes
• Type 2 diabetes accounts for greater than 90% of cases. Type 2 diabetes
is influenced by genetic factors, aging, obesity, and peripheral insulin
resistance, rather than autoimmune processes.
 Gestational diabetes
• Gestational diabetes mellitus (GDM); is a form of diabetes that affects
pregnant women, and occurs in 1 in 25 pregnancies worldwide.
• It is caused by the malfunctioning of insulin receptors, due to the presence
of hormones from the placenta.
 Pathophysiology of type 2 diabetes
• The Potentially important mechanisms associated with
type 2 diabetes and insulin resistance include:
• Decreased insulin secretion
• Resistance to and lack of incretin
• High glucagon levels in the blood
• Increased hepatic glucose production
• Increased glucose reabsorption
• Decreased glucose uptake
• Increased breakdown of lipids within fat cells
• Inappropriate regulation of metabolism by the central
nervous system.
T2DM: Risk Factors
Comparison of type 1 and type 2
diabetes.
Diabetic complications
Lab; Diagnosis of diabetes
Pharmacological Treatment of T2DM
 Pharmacological Treatment of DM
• Insulin:
• Physiological action: Insulin secreted from β-cells
directly in an unbound form, having half life 6
minutes so cleared from the blood rapidly.
• Effects of insulin on the metabolism of
carbohydrate, fats, and proteins:
• On carbohydrate, it promotes glucose uptake and
utilization, increase hepatic glycogen formation and
inhibits hepatic gluconeogenesis.
• It inhibits lipolysis and increase protein synthesis.
Insulin combinations; Various premixed combinations of human insulin's, such as 70% NPH
insulin plus 30% regular insulin, or 50% of each of these are also available. Use of premixed
combinations decreases the number of daily injections but makes it more difficult to adjust
individual components of the insulin regimen.
 Starting insulin therapy
• there is no standard calculation which will establish the
correct starting dose of insulin ,the usual daily dose is
around 0.5 i.u /kg.
• Body weight, larger doses are needed for overweight
people, those with concurrent illness, very high glucose
concentration, ketosis.
• -Smaller doses are needed for slim people, those who
exercise regularly, and those who have residual insulin
(those in whom oral hypoglycemic drugs are only just
inadequate.
• -Doses above 1 i.u/kg. suggest insulin resistance.
• The total daily dosage is divided by the rule of thirds: two-
thirds before breakfast and one third before the evening
meal; at each time of administration two-thirds
intermediate or long acting insulin and one third of short
acting
 SYNTHETIC AMYLIN ANALOG
• Amylin is a hormone that is co-secreted with insulin from β cells
following food intake.
• It delays gastric emptying, decreases postprandial glucagon secretion,
and improves satiety.
• Pramlintide is a synthetic amylin analog that is indicated as an adjunct
to mealtime insulin therapy in patients with type 1 and type 2 diabetes.
• Pramlintide is administered by subcutaneous injection immediately prior
to meals.
• When pramlintide is initiated, the dose of mealtime insulin should be
decreased by 50% to avoid a risk of severe hypoglycemia.
• adverse effects include nausea, anorexia, and vomiting.
• Pramlintide may not be mixed in the same syringe with insulin, and it
should be avoided in patients with diabetic gastroparesis (delayed
stomach emptying), cresol hypersensitivity, or hypoglycemic
unawareness
 INCRETIN MIMETICS
• Incretin mimetics are a new class of antidiabetes
drugs which involve modulation of the incretin
system. They bind to and activate glucagon-like
peptide-1 (GLP-1) receptors on pancreatic beta-cells
following which insulin secretion and synthesis are
initiated.
• Incretin hormones are responsible for 60% to 70%
of postprandial insulin secretion.
• Exenatide
• liraglutide
• injectable incretin mimetics used for the treatment
of type 2 diabetes.
• Mechanism of action;
• The incretin mimetics are analogs of GLP-1 that
exert their activity by acting as GLP-1 receptor
agonists.
• These agents improve glucose dependent insulin
secretion,
• slow gastric emptying time,
• reduce food intake by enhancing satiety (a feeling of
fullness),
• decrease postprandial glucagon secretion, and
promote β-cell proliferation.
• Consequently, weight gain and postprandial
hyperglycemia are reduced, and HbA1c levels
decline.
• Pharmacokinetics and fate
• exenatide and liraglutide must be administered
subcutaneously.
• Liraglutide is highly protein bound and has a long half-life,
allowing for once-daily dosing without regard to meals.
• Exenatide is eliminated mainly via glomerular filtration and
has a much shorter half-life. Because of the short duration of
action, exenatide should be injected twice daily within 60
minutes prior to morning and evening meals.
• A once-weekly extended-release preparation is also available.
• Exenatide should be avoided in patients with severe renal
impairment.
• Adverse effects
• nausea,vomiting, diarrhea, and constipation.
• Exenatide and liraglutide have been associated with
pancreatitis. Patients should be advised to discontinue these
agents and contact their health care provider immediately if
they experience severe abdominal pain
ORAL HYPOGLYCEMIC AGENT
 Sulfonylureas
• glibenclamide (daonil).
• glyburide
• glipizide
• Glimepiride(Amyril)
• Mechanism of action:
• The main mechanism of action includes stimulation of
insulin release from the β cells of the pancreas.
• Sulfonylureas block ATP-sensitive K+ channels, resulting
in depolarization, Ca2+ influx, and insulin exocytosis.
• In addition, sulfonylureas may reduce hepatic glucose
production and increase peripheral insulin sensitivity
• Pharmacokinetics and fate: Given orally, these
drugs bind to serum proteins, are metabolized by
the liver, and are excreted in the urine and feces.
The duration of action ranges from 12 to 24
hours.
• Adverse effects:
• weight gain, hyperinsulinemia, and hypoglycemia.
• They should be used with caution in
• hepatic or renal insufficiency.
• Gliclazide is a safe options in renal dysfunction.
• Glyburide has minimal transfer across the
placenta and may be an alternative to insulin for
diabetes in pregnancy.
Drugs interacting with sulfonylureas
 Biguanides
• Metformin ;
• Mechanism of action:
• 1-metformin is reduction of hepatic
gluconeogenesis.
• 2-Metformin also slows intestinal absorption of
sugars and improves peripheral glucose uptake
and utilization.
• 3-Weight loss may occur because metformin
causes loss of appetite. .
• 4-It increases glucose uptake and use by target
tissues, thereby decreasing insulin resistance.
• Adverse effects:
• 1-These are largely gastrointestinal.
• Metformin is contraindicated in renal dysfunction due
to the risk of lactic acidosis.
• It should be temporarily discontinued in patients
undergoing procedures requiring IV radiographic
contrast.
• Rarely, potentially fatal lactic acidosis has occurred.
• Long-term use may interfere with vitamin B12
absorption.
• Other uses: In addition to type 2 diabetes,
metformin is effective in the treatment of polycystic
ovary syndrome. It lowers insulin resistance seen in
this disorder and can result in ovulation and,
therefore, possibly pregnancy
 Thiazolidinediones
• The thiazolidinediones (TZDs) are also insulin sensitizers.
• pioglitazone
• Rosiglitazone
• The TZDs do not promote its release from the β cells, so
hyperinsulinemia is not a risk.
• Mechanism of action: The TZDs lower insulin resistance by
acting as agonists for the peroxisome proliferator–
activated receptor-γ (PPARγ), a nuclear hormone receptor.
• Activation of PPARγ regulates the transcription of several
insulin responsive genes, resulting in increased insulin
sensitivity in adipose tissue, liver, and skeletal muscle
• Pharmacokinetics and fate;
1. Pioglitazone and rosiglitazone are well absorbed after
oral administration and are extensively bound to
serum albumin.
2. Renal elimination of pioglitazone is negligible, with
the majority of active drug and metabolites excreted
in the bile and eliminated in the feces.
3. Metabolites of rosiglitazone are primarily excreted in
the urine. No dosage adjustment is required in renal
impairment.
4. These agent should be avoided in nursing mothers.
5. Rosiglitazone increases LDL cholesterol and
triglycerides, whereas pioglitazone decreases
triglycerides. Both drugs increase HDL cholesterol
• Adverse effects:
1. A few cases of liver toxicity have been reported with
these drugs, and periodic monitoring of liver function
is recommended.
2. Weight gain can occur because TZDs may increase
subcutaneous fat and cause fluid retention.
3. These drugs should be avoided in patients with severe
heart failure.
4. TZDs have been associated with osteopenia and
increased fracture risk.
5. Pioglitazone may also increase the risk of bladder
cancer.
6. Other uses: As with metformin, the relief of insulin
resistance with the TZDs can cause ovulation to
resume in premenopausal women with polycystic
ovary syndrome.
 α-Glucosidase inhibitors
• Acarbose
• Miglitol
• Mechanism of action:
• Located in the intestinal brush border, α-
glucosidase enzymes break down carbohydrates
into glucose and other simple sugars that can be
absorbed.
• Acarbose and miglitol reversibly inhibit α-
glucosidase enzymes. When taken at the start of a
meal, these drugs delay the digestion of
carbohydrates, resulting in lower postprandial
glucose levels.
• Pharmacokinetics and fate:
• Acarbose is poorly absorbed. It is metabolized
primarily by intestinal bacteria, and some of the
metabolites are absorbed and excreted into the
urine.
• Miglitol is very well absorbed but has no systemic
effects. It is excreted unchanged by the kidney.
• Adverse effects:
• The major side effects are flatulence, diarrhea,
and abdominal cramping.
• Patients with inflammatory bowel disease,
colonic ulceration, or intestinal obstruction
should not use these drugs.
 Dipeptidyl peptidase-4 inhibitors
• Alogliptin
• linagliptin
• saxagliptin
• sitagliptin
• Mechanism of action:
• These drugs inhibit the enzyme DPP-4, which is
responsible for the inactivation of incretin hormones
such as GLP-1. Prolonging the activity of incretin
hormones increases insulin release in response to
meals and reduces inappropriate secretion of glucagon.
• Unlike incretin mimetics, these drugs do not cause
satiety, or fullness, and are weight neutral.
• Pharmacokinetics and fate:
• The DPP-4 inhibitors are well absorbed after oral
administration. Food does not affect the extent of absorption.
• Alogliptin and sitagliptin are mostly excreted unchanged in
the urine.
• Saxagliptin is metabolized via CYP450 3A4/5 to an active
metabolite.
• The primary route of elimination for saxagliptin and the
metabolite is renal.
• Linagliptin is primarily eliminated via the enterohepatic
system.
• All DPP-4 inhibitors except linagliptin require dosage
adjustments in renal dysfunction.
• 3. Adverse effects:
• nasopharyngitis
• headache.
SGLT2-Inhibitors For Treatment of Type2 Diabetes
Dapagliflozin
Canagliflozin
Empagliflozin

Benefits
*Insulin Independent action
*Low hypoglycemic risk
*Weight loss due to caloric loss
• Mechanism of action:
• The sodium–glucose cotransporter 2 (SGLT2) is
responsible for reabsorbing filtered glucose in
the tubular lumen of the kidney. By inhibiting
SGLT2, these agents decrease reabsorption of
glucose, increase urinary glucose excretion, and
lower blood glucose.
• Inhibition of SGLT2 also decreases reabsorption
of sodium and causes osmotic diuresis.
• Therefore, SGLT2 inhibitors may reduce systolic
blood pressure. However, they are not
indicated for the treatment of hypertension.
• Pharmacokinetics and fate:
• These agents are given once daily in the morning.
• Canagliflozin should be taken before the first meal
of the day.
• Both drugs are mainly metabolized by
glucuronidation to inactive metabolites.
• While the primary route of excretion for
canagliflozin is via the feces, about one-third of a
dose is renally eliminated.
• These agents should be avoided in patients with
renal dysfunction
 SGLT2-Inhibitors
Adverse-Effects
Infections Hypotension Tiredness
SGLT2 SGLT2
inhibitors inhibitors The
induce Increased
Induce glycosuria
glycosuria hypotension can lead to
thus can increased
Increases result in urination
chances of Dizziness and
getting Urinary tiredness
Tract
Infections
Diabetic Ketoacidosis
seminar