Module 8: Drugs for Diabetes

Question 1

Insulin Physiology

Answer 1

-pivotal hormone in the regulation of blood glucose levels

Question 2

Synthesis of Insulin

Answer 2

Biosynthesis of Insulin

Insulin is synthesized in the β-cells of the Islets of Langerhans in the pancreas. The process begins with the transcription of the INS gene to produce preproinsulin mRNA, which is then translated into preproinsulin, a precursor molecule. Preproinsulin undergoes sequential enzymatic modifications: first, the removal of its signal peptide to form proinsulin, and subsequently, the cleavage of C-peptide to produce mature insulin. This mature insulin, composed of an A and a B chain linked by disulfide bonds, is stored in secretory granules within the β-cells until secretion is triggered.

Question 3

Secretion of Insulin

Answer 3

Insulin secretion is primarily regulated by blood glucose levels through a glucose-sensing mechanism in β-cells. When blood glucose levels rise (e.g., after a meal), glucose is taken up by β-cells through the GLUT2 transporter. Glucose metabolism within these cells leads to an increase in ATP production, which in turn closes ATP-sensitive potassium channels, causing cell depolarization. This depolarization opens voltage-gated calcium channels, leading to calcium influx and triggering the exocytosis of insulin-containing granules into the bloodstream.

Question 4

Metabolic Actions of Insulin

Answer 4

Insulin facilitates the uptake and utilization of glucose by cells, especially in muscle and adipose tissues, through the activation of GLUT4 glucose transporters. It promotes the synthesis of glycogen in liver and muscle cells (glycogenesis) and inhibits glycogen breakdown (glycogenolysis). Insulin also enhances lipid synthesis (lipogenesis) and inhibits lipolysis, reducing free fatty acid levels in the blood. Additionally, it stimulates protein synthesis and inhibits protein degradation, supporting growth and repair processes.

Question 5

Metabolic Consequences of Insulin Deficiency

Answer 5

Metabolic Consequences of Insulin Deficiency
Insulin deficiency, as seen in type 1 diabetes or advanced type 2 diabetes, shifts the body into a catabolic mode, characterized by:

Increased Glycogenolysis: The breakdown of glycogen into glucose in the liver is enhanced, contributing to hyperglycemia.

Increased Gluconeogenesis: The liver increases the production of glucose from non-carbohydrate sources, further elevating blood glucose levels.

Reduced Glucose Utilization: Without sufficient insulin, glucose cannot be efficiently taken up by muscle and fat cells, exacerbating hyperglycemia.

Ketogenesis: Lipid breakdown increases due to the reduced inhibitory effect of insulin on lipolysis, leading to an excess of free fatty acids in the liver. These are converted into ketone bodies, which can accumulate and cause ketoacidosis, a life-threatening condition.

Question 6

Types of Insulin

Answer 6

Short duration: Rapid acting
 Insulin lispro [Humalog]
 Insulin aspart [NovoLog]
 Insulin glulisine [Apidra]

Short duration: Slower acting
 Regular insulin [Humulin R, Novolin R]
 Intermediate duration
 Neutral protamine Hagedorn (NPH) insulin

Long duration
 Insulin glargine
 Insulin determir [Levemir]

Question 7

Short-Duration,
Rapid-Acting Insulin

Answer 7

Insulin lispro [Humalog]
 Analog of human insulin
 Rapid onset (10 to 20 minutes)
 Short duration (3 to 5 hours)
 Administered immediately before eating or even after eating

 Insulin aspart [NovoLog]
 Insulin lispro [Humalog]
 Rapid-acting analog of regular insulin
 Onset: 15 to 30 minutes after subcutaneous (subQ)
injection
 Duration: 3 to 6 hours
 Usual route is subQ via injection or use of an insulin pump
 Acts faster than regular insulin but has a shorter duration of action
 Should be injected 5 to 10 minutes before meal

Insulin glulisine [Apidra]
 Synthetic analog of natural human insulin
 Rapid onset (10 to 15 minutes)
 Short duration (3 to 5 hours)
 Should be administered close to the time of eatin

Question 8

Short-Duration,
Slower-Acting Insulin

Answer 8

Regular insulin [Humulin R, Novolin R]
 Unmodified human insulin
 Four approved routes: SubQ injection, subQ infusion,
intramuscular (IM) injection (used rarely), and oral
inhalation (approved but not currently used)
 Effects begin in 30 to 60 minutes
 Peak in 1 to 5 hours
 Duration up to 10 hours
 Clear solution

 U-100 (100 units/mL)
 U-500 (500 units/mL)

Question 9

Intermediate-Duration Insulin

Answer 9

NPH insulin [Humulin N, Novolin N]
 Drug is injected twice or 3 times daily to provide
glycemic control between meals and during the night
 NPH insulin is the only one suitable for mixing with
short-acting insulins
 Allergic reactions are possible
 NPH insulins are cloudy suspensions that must be
agitated before administration
 NPH insulins are administered by subQ injection only

Question 10

Long-Duration Insulin

Answer 10

Insulin glargine [Lantus]
 Modified human insulin
 Prolonged duration of action (up to 24 hours)
 Once-daily subQ dosing to treat adults and children
with type 1 diabetes and adults with type 2 diabetes
 Clear solution

Insulin detemir [Levemir]
 Human insulin analog
 Slow onset and dose-dependent duration of action
 Used to provide basal glycemic control
 Clear, colorless solution
Dosing: Once or twice daily by subQ injection
 Do not mix with other insulins
 Must not be given IV

Question 11

Insulin Appearance

Answer 11

Except for NPH insulins, all insulins made in the
United States are formulated as clear, colorless
solutions
 NPH insulin is a cloudy suspension
 Patients should inspect their insulin before using
it and should discard the vial if the insulin looks
abnormal

Question 12

Insulin Administration

Answer 12

Concentration
 100 units/mL (U-100)
 500 units/mL (U-500)

Mixing insulins
 NPH with short-acting insulins
 Short-acting insulin drawn first

Subcutaneous injection
 Syringe and needle
 Pen injectors
 Jet injectors

Subcutaneous infusion
 Portable insulin pumps
 Implantable insulin pumps
 Intravenous infusion
 Inhalation

Question 13

Insulin Therapy of Diabetes

Answer 13

Dosage
 Dosing schedules
 Three dosing schedules
* Twice daily premixed insulin regimen
* Intensive basal/bolus strategy
* Continuous subcutaneous insulin

Question 14

Complications of Insulin Treatment

Answer 14

Hypoglycemia: Blood glucose below 70 mg/dL
 Drug interactions
 Blood glucose below 70 mg/dL
* Rapid treatment mandatory
* Conscious patients: Fast-acting oral sugar (eg, glucose
tablets, orange juice, sugar cubes, nondiet soda)
* If swallowing reflex or gag reflex is suppressed:
 Nothing should be given by mouth
 IV glucose or parenteral glucagon is the preferred treatment

 Lipohypertrophy (Lipohypertrophy is a medical condition characterized by an abnormal accumulation of fat in specific areas of the body, creating lumps or fatty masses beneath the skin’s surface. This condition often arises as a complication of insulin therapy for diabetes, where repeated injections of insulin in the same area lead to localized increases in subcutaneous fat tissue.)
 Allergic reactions
 Hypokalemia
 Drug interactions
 Hypoglycemic agents
 Hyperglycemic agents
 Beta-adrenergic blocking agent

Question 15

Oral Hypoglycemics

Answer 15

Biguanides
 Metformin [Glucophage]
 Sulfonylureas
 Thiazolidinediones (also known as glitazones)
Rosiglitazone [Avandia]
Pioglitazone [Actos]
 Meglitinides (also known as glinides)
Repaglinide [Prandin]
Nateglinide [Starlix]

Question 16

Biguanides

Answer 16

Biguanides
 Metformin [Glucophage]
* Drug of choice for initial therapy in most patients with type 2 diabetes
* Most common side effects: Gastrointestinal (GI) disturbances
* Lactic acidosis, a potentially fatal complication, is rare
* Prevention of type 2 diabetes
* Gestational diabetes
* Polycystic ovary syndrome (PCOS)
* Drug interactions

Question 17

Sulfonylureas

Answer 17

Sulfonylureas
 First oral antidiabetics available
 Promote insulin release
 Can be used only for type 2 diabetes
 Major side effects: Hypoglycemia, weight gain
 First generation
 Second generation
 Cardiotoxicity
 Drug interactions

Question 18

Meglitinides (glinides)

Answer 18

Meglitinides (glinides)
 Repaglinide [Prandin]
* Generally well tolerated
* Adverse effect: Hypoglycemia
* Drug interactions: Gemfibrozil [Lopid]
 Nateglinide [Starlix]
* Pharmacology nearly identical to that of repaglinide

Question 19

Thiazolidinediones (glitazones)

Answer 19

Thiazolidinediones (glitazones)
 Reduce glucose levels primarily by decreasing insulin
resistance
 Only indication is type 2 diabetes, mainly as an add-
on to metformin
 Rosiglitazone [Avandia]: Restricted use
 Pioglitazone [Actos

Question 20

Pioglitazone [Actos]

Answer 20

Pioglitazone [Actos]
 Reduces insulin resistance and may also decrease
glucose production
 Indication: Adjunct to diet and exercise to improve
glycemic control in adults with type 2 diabetes
 Adverse effects: Generally well tolerated; most
common reactions are upper respiratory tract
infection, headache, sinusitis, and myalgia
 Drug interactions

Question 21

Alpha-glucosidase inhibitors

Answer 21

Alpha-glucosidase inhibitors
 Act in the intestine to delay absorption of
carbohydrates
 Indication: Type 2 diabetes
 Acarbose [Precose]
* Adverse effects: Frequently causes flatulence, cramps,
abdominal distention, borborygmus, and diarrhea, liver dysfunction

Question 22

Miglitol [Glyset]

Answer 22

Miglitol [Glyset]
* Especially effective among Latinos and African Americans
* Adverse effects: Flatulence, abdominal discomfort, and other GI effects
* Has not been associated with liver dysfunction

Question 23

DPP-4 inhibitors (also called gliptins)

Answer 23

DPP-4 inhibitors (also called gliptins)
 Promote glycemic control by enhancing the actions of incretin hormones
 Stimulate glucose-dependent release of insulin
 Suppress postprandial release of glucagon
 Sitagliptin [Januvia]

Question 24

Saxagliptin [Onglyza]

Answer 24

Saxagliptin [Onglyza]
* Most common adverse effects: Upper respiratory infection, urinary tract infection, and headache
 Linagliptin [Tradjenta]
 Alogliptin [Nesina]

Question 25

Sodium-glucose co-transporter 2 (SGLT-2)
inhibitors

Answer 25

Sodium-glucose co-transporter 2 (SGLT-2)
inhibitors
 Block reabsorption of filtered glucose in the kidney,
leading to glucosuria
 Indication: Type 2 diabetes mellitus
 Canagliflozin [Invokana]
* Side effects: Genital fungal infections in female patients, urinary tract infections, increased urination

Question 26

Dapagliflozin [Farxiga]

Answer 26

Dapagliflozin, marketed under the brand name Farxiga, is a medication used to treat type 2 diabetes and, in some cases, heart failure. It belongs to a class of drugs known as sodium-glucose cotransporter 2 (SGLT2) inhibitors. SGLT2 is a protein in the kidneys that facilitates glucose reabsorption into the bloodstream. By inhibiting this protein, dapagliflozin promotes the excretion of glucose through urine, thereby lowering blood glucose levels in individuals with type 2 diabetes.

Question 27

Other Drugs
Colesevelam [Welchol]
 Bromocriptine

Answer 27

Colesevelam (Welchol)
Colesevelam is a medication classified as a bile acid sequestrant. It’s primarily used to treat high cholesterol and to improve glycemic control in adults with type 2 diabetes mellitus, often in combination with other medications.

Bromocriptine
For Diabetes: Bromocriptine is a dopamine D2 receptor agonist. Its use in diabetes is based on the concept of resetting the biological clock, which may be related to circadian rhythms of neurotransmitter action in the brain. It’s thought to reduce insulin resistance and glucose production in the liver. Its precise mechanism for improving glycemic control is not fully understood but involves modulation of dopaminergic and possibly serotonergic pathways.

Question 28

Non-Insulin Injectable Drugs
 Pramlintide - Amylin mimetic

Answer 28

 Pramlintide
Pramlintide is a synthetic analogue of amylin, a hormone that is naturally secreted by the pancreatic β-cells along with insulin in response to food intake. Because pramlintide acts as an amylin mimetic, it is used in the treatment of diabetes to complement insulin therapy. Amylin plays several roles in glucose regulation, including the modulation of gastric emptying, suppression of postprandial glucagon secretion, and enhancement of satiety, which helps to reduce food intake. By mimicking these actions, pramlintide aids in the management of blood glucose levels.

Mechanism of Action:
Slows Gastric Emptying: Pramlintide delays the rate at which food empties from the stomach into the small intestine, resulting in a slower and more gradual absorption of glucose into the bloodstream.

Suppresses Glucagon Secretion: After meals, pramlintide inhibits the secretion of glucagon, a hormone that raises blood glucose levels by promoting the release of glucose stored in the liver. By suppressing glucagon, pramlintide helps to prevent the postprandial rise in blood glucose.

Enhances Satiety: Pramlintide promotes a feeling of fullness, leading to a reduction in food intake and potentially aiding in weight management, which is beneficial for individuals with type 2 diabetes.

Question 29

Non Insulin Injectable Drugs
GLP1 meds

Answer 29

GLP-1 receptor agonists (also called incretin
mimetics)
 Slow gastric emptying, stimulate glucose-dependent
release of insulin, inhibit postprandial release of
glucagon, and suppress appetite
 Exenatide [Byetta]
* Adverse effects: Hypoglycemia and gastrointestinal effects, including pancreatitis
* Drug interactions

Liraglutide [Victoza]
* May cause medullary thyroid carcinoma (MTC)

Question 30

Acute Complications of
Poor Glycemic Control

Answer 30

 Diabetic ketoacidosis (DKA)
 Hyperosmolar hyperglycemic state (HHS)
 Cardinal features of both conditions: Hyperglycemic
crisis and associated loss of fluid and electrolytes
 Both conditions can be life-threatening

Differences
 Hyperglycemia more severe in HHS
 Ketoacidosis characteristic of DKA, absent in HHS
 Treatment of the two disorders is similar

Question 31

Diabetic Ketoacidosis

Answer 31

Severe manifestation of insulin deficiency
 Symptoms evolve quickly within hours or days
 Most common complication in pediatric patients and
leading cause of death

Characteristics
 Hyperglycemia
 Ketoacids
 Hemoconcentration
 Acidosis
 Coma

Question 32

Hyperosmolar Hyperglycemic
State (HHS)

Answer 32

Also called hyperglycemic hyperosmolar
nonketotic syndrome (HHNS)
 Large amount of glucose excreted in urine
 Results in dehydration and loss of blood volume
 Increases blood concentrations of electrolytes
and nonelectrolytes (particularly glucose); also
increases hematocrit
 Blood “thickens” and becomes sluggish

Little or no change in ketoacid levels
 Little or no change in blood pH
 No sweet or acetone-like smell to urine or breath
 Occurs most frequently with type 2 diabetes with
acute infection, acute illness, or some other
stress

Can evolve slowly
 Metabolic changes begin a month or two before signs and symptoms become apparent
 If left untreated, can lead to coma, seizures, and
death
 Management
 Correct hyperglycemia and dehydration with IV
insulin, fluids, and electrolytes