diabeties

Question 1

What are the types of diabetes

Answer 1

1) Type 1 diabetes (formerly insulin-dependent diabetes mellitus)

2) Type 2 diabetes (formerly non–insulin dependent diabetes
mellitus)

3) Gestational diabetes

4) Diabetes due to other causes such as genetic defects or
medications or endocrinopathies.

Question 2

What is the treatment for type 1 DM

Answer 2

Type 1 diabetes
• Requires exogenous insulin to maintain blood glucose
concentrations as close to normal as possible and
acceptable levels of glycosylated hemoglobin (HbA1c).

Question 3

What is type 2 DM

Answer 3

• Type II diabetes may remain undetected for years.
• At the onset of the disease, insulin levels can be high, normal,
or low.
• The major cause is a lack of sensitivity of target organs to
insulin (insulin resistance).
• The pancreas retains some β-cell function, but insulin secretion
is insufficient to maintain glucose homeostasis
• Obesity contributes to insulin resistance, which is considered
the major underlying defect of type 2 diabetes.
• The goal in treating type 2 diabetes is to maintain blood
glucose within normal limits and to prevent the development of
long-term complications.

Question 4

What is the treatment of type 2 DM

Answer 4

• Weight reduction, exercise, and dietary modification decrease
insulin resistance and correct hyperglycemia in some patients
with type 2 diabetes.
• However, most patients require pharmacologic intervention
with oral glucose-lowering agents.
• As the disease progresses, β-cell function declines and insulin
therapy is often needed to achieve satisfactory glucose levels.
• Administration of insulin preparations or oral hypoglycemic
agents is associated with decreased morbidity & mortality.

Question 5

What is insulin and what’s its precursor

Answer 5

• Insulin is a polypeptide hormone.
• It is synthesized as a precursor (proinsulin) that undergoes
proteolytic cleavage to form insulin and C-peptide, both of which are
secreted by the β cells of the pancreas.

Question 6

How is insulin secreted

Answer 6

• Secretion is most often triggered by increased blood glucose, which
is taken up by the glucose transporter into the β cells of the pancreas.
→phosphorylated by glucokinase, which acts as a glucose sensor.
→The products of glucose metabolism enter the mitochondrial
respiratory chain and generate ATP.
→blockade of K+ channels
→membrane depolarization
→influx of Ca2+
→The increase in intracellular Ca2+ causes pulsatile insulin exocytosis

Question 7

How do we make human insulin

Answer 7

Human insulin is produced by recombinant DNA technology using
strains of Escherichia coli or yeast that are genetically altered to contain
the gene for human insulin

Question 8

How do we change the kinetics of insulin

Answer 8

Modification of the amino acid sequence of human insulin

Question 9

What affects the insulin administration

Answer 9

Dose, injection site, blood supply, temperature, and physical activity

Question 10

How do we administrator insulin

Answer 10

• Generally by SC.
• In a hyperglycemic emergency, short acting insulins are injected IV.
• Continuous SC insulin infusion (also called the insulin pump) is
another method of insulin delivery.
• The pump is programmed to deliver a basal rate of insulin.
• It is inactivated by insulin protease, which is found mainly in the liver
and kidneys → may need to adjust dose in renal insufficiency.

Question 11

Afrezza is ultra short acting

Question 12

What are the side effects of insulin

Answer 12

• Insulin has a narrow therapeutic window.
• Hypoglycemia
• Weight gain, lipodystrophy

Question 13

Hypoglycemia: who are higher risk?

Answer 13

• Patients with advanced renal disease,
• the elderly,
• children younger than 7 years are most
susceptible to the detrimental effects of
hypoglycemia.

Question 14

How do we fight hypoglycemia

Answer 14

• Oral candy or sugar or IV glucose should
be administered.
• IM glucagon can be used for severe cases.

Question 15

What are the short (rapid) insulin

Answer 15

• Regular insulin, insulin lispro, insulin aspart, and insulin
glulisine

Question 16

What is regular insulin

Answer 16

• Regular insulin is a short-acting, soluble, crystalline zinc insulin.

Regular insulin should be injected SC 30 min before a meal for
the rise in circulating insulin to match the rise in blood glucose
following meal

Pregnancy category B

Peak level 50-120 mins

Mimics the postprandial insulin

Question 17

What are Insulin lispro, aspart, and glulisine

Answer 17

rapid-acting
insulins.
insulin lispro, and insulin aspart are pregnancy
category B.
• Insulin glulisine is pregnancy category C.
The lispro, aspart, & glulisine offer more flexible treatment
regimens and may lower the risk of hypoglycemia
Insulin lispro differs from regular insulin in that lysine and
proline at positions 28 and 29 in the B chain are reversed
➔ more rapid absorption, a quicker onset, and a shorter duration of
action after SC injection.
• Peak levels of insulin lispro are seen at 30 to 90 minutes after
injection

control postprandial
glucose.

Question 18

What are the intermediate acting insulin

Answer 18

Neutral protamine Hagedorn insulin (NPH, isophane insulin)• A suspension of crystalline zinc insulin combined with a positively
charged polypeptide, protamine.
• The combination with protamine forms a complex that is less soluble,
resulting in delayed absorption and a longer duration of action?
• NPH insulin should be given only SC, never IV.
• It is used for basal (fasting) control in type 1 or 2 diabetes and is
usually given along with rapid- or short-acting insulin for mealtime
Control.
• It should not be used when rapid glucose lowering is needed

Neutral protamine lispro (NPL) insulin for combination with insulin
lispro.

Lente insulin:An amorphous precipitate of insulin with zinc ion in acetate buffer
(Semilente insulin) combined with 70% Ultralente insulin.

Question 19

What are the long acting insulins

Answer 19

a) Insulin glargine: the isoelectric point of insulin glargine is lower than
human insulin
→ precipitation at the injection site that releases insulin over an extended
period.
• It is slower in onset than NPH insulin and has a flat, prolonged
hypoglycemic effect (has no peak).

b) Insulin detemir: has a fatty acid side chain that enhance association
with albumin and self-aggregation in s.c. tissue
• Slow dissociation from albumin results in long-acting properties.
These forms are peakless & do not cause hypoglycemia.

c) Ultralente insulin: a suspension of zinc insulin in acetate buffer giving
large particles that are slow to dissolve.
• insulin glargine and insulin detemir are used for basal control and
should only be administered SC.
• Neither long-acting insulin should be mixed in the same syringe with
other insulins. Due to the possible change in pharmacokinetics

Question 20

What are the different insulin combinations

Answer 20

• 70% NPH insulin + 30% regular insulin
• 50% NPH insulin + 50% regular insulin
• 75% NPL insulin + 25% insulin lispro

Question 21

Why do we use insulin combinations

Answer 21

Use of premixed combinations decreases the number of daily
injections but makes it more difficult to adjust individual
components of the insulin regimen.

Question 22

What is Amylin

Answer 22

Amylin is a hormone that is cosecreted with insulin from pancreatic
β cells following food intake.
• It delays gastric emptying, decreases postprandial glucagon
secretion, and improves satiety

Question 23

What is Pramlintide

Answer 23

synthetic analog of amylin, may be used as an
adjunct to mealtime insulin therapy in patients with type 1 and type 2
diabetes to control postprandial glucose level.
• Has short duration of action.
• Pramlintide MOA:
1) slows gastric emptying, thus slowing absorption of glucose
2) promotes satiety via hypothalamic receptors
3) inhibits secretion of glucagon
• Given SC & should be injected 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.
• Major A/E: hypoglycemia. nausea, anorexia, and vomiting.
• Should not be given to patients with diabetic gastroparesis
(delayed stomach emptying), cresol hypersensitivity, or
hypoglycemic unawareness.

Question 24

What is the Incretin effect

Answer 24

Oral glucose results in a higher secretion of insulin than
occurs when an equal load of glucose is given IV.
markedly reduced in type 2 diabetes.
• The incretin effect occurs because the gut releases incretin
hormones, notably glucagon-like peptide-1 (GLP-1), in
response to a meal.
• Incretin hormones are responsible for 60% to 70% of
postprandial insulin secretion.

Question 25

What is the MOA for the Incretin mimetics (GLP-1)

Answer 25

• 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 -cell proliferation.
• Consequently, postprandial hyperglycemia is reduced, A1C levels
decrease, and weight loss may occur.

Question 26

What are the GLP-1 AGONISTS (tide)

Answer 26

Dulaglutide, exenatide ,liraglutide , lixisenatide , semaglutide
All injectable for type 2
Semaglutide is also available in an oral formulation.]
• Dulaglutide, liraglutide, and semaglutide are also approved to
reduce the risk of cardiovascular mortality in patients with type 2
diabetes and cardiovascular disease.
• Two premixed preparations of long-acting insulins and GLP-1
receptor agonists are available:
• insulin glargine plus lixisenatide and insulin deglude plus
liraglutide.
• Use of these combinations may decrease daily insulin
requirements and the number of daily injections.
Higher dosages of injectable semaglutide and liraglutide are
approved for the treatment of obesity

Question 27

What are the pharmacokinetics for GLP1

Answer 27

Dulaglutide, semaglutide and ,liraglutide , are
considered long- acting
• Dulaglutide, semaglutide are dosed once weekly
• Liraglutide is dosed once-daily injection
• Oral formulation of semaglutide once daily
• Lixisenatide is short acting dosed once daily
• Exenatide is available as both short-acting (BID)
and extended- release preparation( once weekly)
• Exenatide should be avoided in patients with severe
renal impairment.

Question 28

What are the side effects for GLP 1 agonists

Answer 28

• Main : nausea, vomiting, & diarrhea.
• Associated with pancreatitis, should be avoided in
  patients with chronic pancreatitis
• Exenatide has caused serious and sometimes fatal
  pancreatitis
• Hypoglycemia when exenatide is combined with
  sulfonylureas.
• Long- acting agents have been associated with certain
  thyroid tumors in rodents .

Question 29

What are insulin secretagogues

Answer 29

Sulfonylureas & Meglitinides (glinides) increase insulin
secretion

Question 30

What are the sulfonylureas (ide)

Answer 30

• Secretagogues.
• Mainly tolbutamide & the second-generation drugs, glyburide,
glipizide, & glimepiride.
• MOA:
• 1) Stimulation of insulin release from the β cells of the pancreas by
blocking the ATP-sensitive K+ channels, resulting in depolarization,
Ca2+ influx, and insulin exocytosis.
2) Reduction in hepatic glucose production
3) Increase in peripheral insulin sensitivity.
• Pharmacokinetics: bind to serum proteins, metabolized by liver, &
excreted in the urine and feces.
• Give with meals-single dose with breakfast, or divided doses for ones
with shorter durations
• 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, since accumulation may cause
hypoglycemia.
• Renal impairment is a particular problem for
glyburide, as it may increase the duration of action
and increase the risk of hypoglycemia significantly
• Glipizide or glimepiride are safer options in renal
dysfunction and in elderly patients because they are
metabolized to inactive metabolites.
• Glyburide has minimal transfer across the placenta and may be
a reasonably safe alternative to insulin therapy for diabetes in
pregnancy.
• Pregnancy category C, while Insulin is Pregnancy Category B.
• Sulfonylureas shouldn’t be used during breast-feeding.

Question 31

What are GLINIDES

Answer 31

Meglitinides, Short-acting insulin secretagogues
• Repaglinide & nateglinide
• They are particularly effective in the early release of insulin that
occurs after a meal and are categorized as postprandial glucose
regulators.
• MOA:
• they bind to a distinct site on the β cell, closing ATP-sensitive K+
channels, thereby initiating a series of reactions that results in the
release of insulin.
• In contrast to the sulfonylureas, the glinides have a rapid onset and
a short duration of action.
• Combined with metformin or the glitazones.
• Should not be combined with sulfonylureas due to overlapping
mechanisms of action. This would increase the risk of serious
hypoglycemia.
• Pharmacokinetics:
• Glinides should be taken prior to a meal and are well
absorbed after oral administration.
• Both glinides are metabolized to inactive products by
CYP3A4 in the liver and are excreted through the
bile.
• Adverse effects:
• can cause hypoglycemia and weight gain, the incidence is lower than
that with sulfonylureas.
• Drugs that inhibit CYP3A4, such as:
• itraconazole, fluconazole, erythromycin, and clarithromycin, may
enhance the glucose-lowering effect of repaglinide.
• Drugs that induce CYP3A4, such as:
• barbiturates, carbamazepine, and rifampin, may have the opposite
effect.
• Repaglinide has been reported to cause severe hypoglycemia in
patients who are also taking the lipid-lowering drug gemfibrozil
(enzyme inhibition) and concurrent use is contraindicated..
• Caution in patients with hepatic impairment.
• C/I in pregnancy & lactation.

Question 32

What are insulin sensitizers

Answer 32

• Biguanides and thiazolidinediones :
• lower blood sugar by improving target-cell response to insulin
without increasing pancreatic insulin secretion.
• It increases glucose uptake and use by target tissues, thereby
decreasing insulin resistance.

Question 33

What are biguanides (Metformin)

Answer 33

• MOA:
1) Main:↓ Hepatic glucose output by inhibiting hepatic gluconeogenesis
(accounting for the high fasting blood glucose in type 2 DM)
2) Slows intestinal absorption of sugars
3) Improves peripheral glucose uptake and utilization (decreasing
insulin resistance).
4) Causes loss of appetite→ weight loss.
5) ↓ Hyperlipidemia (↓ LDL & ↑ HDL): these effects may not be
apparent until 4 to 6 weeks of use.
The ADA treatment algorithm recommends metformin as the drug of
choice for newly diagnosed Type 2 diabetics.
Metformin may be used alone or in combination with one of the other
oral agents or insulin.
Combination with insulin has the advantage of reducing weight gain
that results from insulin
• Pharmacokinetics:
• Metformin is well absorbed orally,
• not bound to serum proteins, not metabolized.
• Excretion is via the urine.??
• Given 3 times a day with meals.
• Maximum dose: 850 mg x 3 (gradual titration).

Question 34

What are the side effects for Metformin

Answer 34

• These are largely gastrointestinal.??
• Does not promote insulin secretion
→the risk of hypoglycemia is far less than that with sulfonylurea
agents, and it may only occur if caloric intake is not adequate or
exercise is not compensated for calorically.
→If used with insulin, the dose of insulin may require adjustment,
because metformin decreases the production of glucose by the liver.
Metformin is contraindicated in renal dysfunction due to the
risk of lactic acidosis.
• Most dangerous A/E is lactic acidosis (rarely)→
• Contraindicated in diabetics with :
• renal dysfunction, hepatic disease, exacerbation of HF, acute
MI (because of hypoperfusion), diabetic ketoacidosis, severe
infection, sepsis, dehydration,
• other disorders that may cause acute renal failure .
• In severe infection and other acute stresses, oral
hypoglycemics are stopped and insulin is initiated).
• Should be temporarily discontinued in patients undergoing
diagnosis requiring IV radiographic contrast agents, because
use of such products may result in acute alteration of renal
function.
• Should be used with caution in patients greater than 80 years
of age (check renal function) or in those with HF or alcohol
abuse.
• Long-term use may interfere with vitamin B12 absorption.

Question 35

The onset of lactic acidosis often is subtle, and accompanied
only by nonspecific symptoms such as malaise, myalgias,
respiratory distress, increasing somnolence, and nonspecific
abdominal distress. There may be associated hypothermia,
hypotension, and resistant bradyarrhythmias with more marked
acidosis.

Question 36

What are the other uses for Metformin

Answer 36

1) metformin is effective in the treatment of polycystic ovary
disease. Its ability to lower insulin resistance in these women can
result in ovulation and, possibly, pregnancy.
Polycystic ovary syndrome (PCOS), also called hyperandrogenic
anovulation (HA) is a set of symptoms due to a hormone imbalance in
women.
Symptoms include: irregular or no menstrual periods, heavy periods,
excess body and facial hair, acne, pelvic pain, & trouble getting
pregnant, obesity , higher risk of prediabetes
• 2) Recent clinical trials suggest that metformin decreases the risk of
diabetes in high risk patients (prediabetic persons).

Question 37

What are Thiazolidinions (glitazines)

Answer 37

• Pioglitazone & rosiglitazone.
• MOA: 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( that affect glucose and lipid homeostasis)
→ increase insulin sensitivity in adipose tissue, liver, and skeletal muscle.
→ In DM the major site is adipocytes:
↓adipocyte production and secretion of fatty acids & ↑ glucose metabolism
• They lead to a favorable redistribution of fat from visceral to subcutaneous
tissues.
• Rosiglitazone increases LDL cholesterol and triglycerides, whereas
pioglitazone decreases triglycerides. Both drugs increase HDL
cholesterol.
• TZDs can be used as monotherapy or in combination with other
hypoglycemics or with insulin.
• The ADA recommends pioglitazone as a second- or third-line agent
for type 2 diabetes.
• Rosiglitazone is less utilized due to concerns regarding cardiac
adverse effects.
• Pharmacokinetics:
• Pioglitazone and rosiglitazone are well absorbed after oral
administration
• extensively bound to serum albumin.
• Both undergo extensive metabolism by different CYP450 isozymes.
Some metabolites of pioglitazone have activity.
• Pioglitazone and metabolites excreted in the bile and eliminated in
the feces.
• Metabolites of rosiglitazone are primarily excreted in the urine.
• Caution with rosiglitazone if creatinine clearance < 30 mL/min.

Question 38

What are the side effects for TZD

Answer 38

• Measure liver enzyme initially and periodically thereafter.
• Weight gain, possibly through the ability of TZDs to increase
subcutaneous fat & cause fluid retention (can worsen HF).
• Osteopenia and increased fracture risk in females.
• Several meta-analyses identified a potential increased risk of MI and
death from cardiovascular causes with rosiglitazone.
• TZDs reduce plasma concentrations of the estrogen-containing
contraceptives.
• These agents should be avoided in patients with severe heart failure
and in nursing mothers.

Question 39

What are the other uses for TZD

Answer 39

• TZDs can cause ovulation to resume in premenopausal women with
polycystic ovary syndrome.
• Recent clinical trials suggest that TZDs decrease the risk of diabetes
in high risk patients.
• Have fallen out of favor in recent years

Question 40

What are α-Glucosidase Inhibitors:
(Acarbose & miglitol)

Answer 40

Orally active. For type 2 diabetes.
• MOA:
• 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.
• Taken at the beginning of meals
→ Inhibit:
a) Membrane-bound α-glucosidase in the intestinal brush border (the enzyme
responsible for the hydrolysis of oligosaccharides to glucose and other
sugars)
b) Pancreatic α-amylase, thus interfering with the breakdown of starch to
oligosaccharides.
→ delay the digestion of carbohydrates, thereby resulting in lower
postprandial glucose levels.
• Do not stimulate insulin release or tissue sensitivity.
• Like metformin & TZDs, α-glucosidase inhibitors have been
shown to prevent diabetes in prediabetic persons.
• Pharmacokinetics:
• Given 3 times daily.
• Acarbose is poorly absorbed.
• It is metabolized primarily by intestinal bacteria, and some of the
metabolites are absorbed and excreted into the urine → avoid if
creatinine cl < 25 mL/min.
• Miglitol is very well absorbed but has no systemic effects.
• It is excreted unchanged by the kidney
• Adverse effects:
• Flatulence , diarrhea, & abdominal cramping.
• C/I in patients with inflammatory bowel disease, colonic
ulceration, or intestinal obstruction.
• As monotherapy, they do not cause hypoglycemia.
However, when used in combination with sulfonylureas
or insulin,…
• It is important that hypoglycemia in this context be
treated with glucose rather than sucrose, because sucrose
is also inhibited by these drugs

Question 41

What are Dipeptidyl Peptidase-IV Inhibitors:
• Alogliptin, Linagliptin, Sitagliptin, Saxagliptin &
Vildagliptin

Answer 41

are orally active DPP-4 inhibitors used for the
treatment of type 2 diabetes.
• MOA:
• 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.
• They may be used as monotherapy or in combination with a sulfonylurea,
metformin, TZDs or insulin.
• Unlike GLP-1 agonist , these drugs do not cause satiety of fullness and so are
weight neutral
• Pharmacokinetics:
• The DPP-4 inhibitors are well absorbed after oral administration.
• 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 (↓ Dose).
• Adverse effects:
• Nasopharyngitis, and headache are the most common
• pancreatitis. ( infrequent)
• No significant incidence of hypoglycemia.
• Hepatic enzyme inhibitors (like clarithromycin) can cause
significant increase in levels of saxagliptin→ reduce dose.

Question 42

What are Sodium-glucose cotransporter 2 inhibitors (SGLT2
inhibitors)
✓ Canagliflozin and dapagliflozin, empagliflozin, ertugliflozin

Answer 42

for
treating of type 2 diabetes
✓ MOA: are oral Sodium Glucose cotransporter 2 inhibitors
➢ SGLT2 is responsible for reabsorbing filtered glucose in the tubular
lumen of the kidney.
➢ So SGLT2 inhibitors ↓ reabsorption of glucose, ↑ urinary glucose
excretion, and ↓ blood glucose.
➢ Also, ↓ reabsorption of Na+ → osmotic diuresis. Figure next slide
➢ So they ↓ BP, but they are not used as a treatment for HTN
✓ Monotherapy or in combination with insulin or other antidiabetics.
✓ Some of these drugs are indicated to reduce CVS death in patients
with type 2 DM and CVS diseases
• Pharmacokinetics:
• These agents are given orally once daily in the morning.
• Canagliflozin should be taken before the first meal of the
day.
• All 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 severe renal
dysfunction.
✓ Adverse effects:
✓ The most common are:
✓ female genital mycotic infections, UTIs, urinary frequency.
✓ Others :
✓ Hypotension in elderly or patients on diuretics.
✓ Ketoacidosis
✓ Increased bone fractions

Question 43

• Other agents:
✓ Dopamine agonist, bromocriptine
✓ Bile acid sequestrant, colesevelam produce modest reduction
in HbA1c.
✓ MOA:
➢ Unknown
➢ Although bromocriptine and colesevelam are indicated for the
treatment of type 2 diabetes, their modest efficacy, adverse effects,
and pill burden limit their use in clinical practice.