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The Pancreas and
Glucose Homeostasis
Diabetes mellitus
DM   is characterized by elevated blood sugar
 levels due to absolute or relative lack of
 insulin.
Type 1 diabetes - β-cell failure at outset
  ◦ Insulin dependent
Type   2 diabetes - Gradual β-cell deterioration
  ◦ Early stages: Diet and Oral agents
  ◦ Late-stage: Insulin therapy
The pancreas and glucose homeostasis l4
The pancreas and glucose homeostasis l4
Glycosylated hemoglobin Hb-A1c

Itis used to monitor the plasma glucose
 concentration over prolonged periods of time (4-6
 weeks).
Insulin secretion is promoted by:
      ◦ ↑ blood glucose levels
      ◦ ↑ amino acids
      ◦ GI hormones
      ◦ β-2 agonist: stimulates
                 glycogenolysis
                 release of glucagon
The pancreas and glucose homeostasis l4
The pancreas and glucose homeostasis l4
Beta cells   Peripheral tissues
Insulin
     Insulin is a storage hormone:
    i. it promotes anabolism
    ii. inhibits catabolism of carbohydrates, fatty
        acids and protein.

     In the absence of insulin:
    i. most tissues cannot use glucose
    ii. 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.
Liver:
1. Insulin increase the storage of glucose as
   glycogen in the liver.
     ◦     It inserts the GLUT-2 glucose transport molecule in
           the cell membrane.
1.       It inhibits gluconeogenesis – thus significantly
         ↓ glucose output by the liver.
2.       It decrease the protein catabolism.
The pancreas and glucose homeostasis l4
Muscle :
1. Insulin stimulates the glycogen synthesis
   and protein synthesis.
     ◦     Glucose transport into the cells is facilitated by
           GLUT-4 into the cell membrane.
1.       It inhibits the protein catabolism.
 Signs and symptoms
The classic symptoms of untreated diabetes are
 loss of weight, polyuria (frequent urination),
 polydipsia (increased thirst) and polyphagia
 (increased hunger).[11] Symptoms may develop
 rapidly (weeks or months) in type 1 diabetes,
 while they usually develop much more slowly and
 may be subtle or absent in type 2 diabetes.

Prolonged high blood glucose can cause glucose
  absorption in the lens of the eye, which leads to
  changes in its shape, resulting in vision changes.
  Blurred vision is a common complaint leading to
  a diabetes diagnosis. A number of skin rashes
  that can occur in diabetes are collectively known
  as diabetic dermadromes.
Diabetic   emergencies

People (usually with type 1 diabetes) may
 also present with diabetic ketoacidosis, a
 state of metabolic dysregulation
 characterized by the smell of acetone, a
 rapid, deep breathing known as
 Kussmaul breathing, nausea, vomiting
 and abdominal pain, and altered states of
 consciousness.
Complications
typically   develop after many years (10–
 20).
damage to blood vessels.
Diabetes doubles the risk of
 cardiovascular disease,
 ”macrovascular" diseases, (related to
 atherosclerosis of larger arteries) include
 ischemic heart disease (angina and
 myocardial infarction), stroke and
 peripheral vascular disease.
Diabetes also damages the capillaries
(causes microangiopathy).
 Diabetic retinopathy, which affects blood
vessel formation in the retina of the eye,
can lead to visual symptoms, reduced
vision, and potentially blindness.

Diabetic nephropathy, the impact of
diabetes on the kidneys, can lead to
scarring changes in the kidney tissue, loss
of small or progressively larger amounts of
protein in the urine, and eventually chronic
kidney disease requiring dialysis.
Diabetic neuropathy is the impact of
diabetes on the nervous system, most
commonly causing numbness, tingling and
pain in the feet and also increasing the risk
of skin damage due to altered sensation.
Together with vascular disease in the legs,
neuropathy contributes to the risk of
diabetes-related foot problems (such as
diabetic foot ulcers) that can be difficult to
treat and occasionally require amputation.
Insulin
 Adipose tissue :
 1. Insulin facilitates the storage of
    triglyceride by:
      i. activating plasma lipoprotein lipase
      ii. inhibiting intracellular lipolysis.
 2.    It increase the glucose uptake by GLUT-4
       insertion into the cell membrane.
Effect of insulin on glucose uptake and
               metabolism




                glycolysis
Insulin is a 51 AA peptide
Not active orally.
Insulin is inactivated by insulinase (insulin
 transhydrogenase ) found mainly in liver and
 kidney.
Dose reduced in renal insufficiency
Sources of Insulin :
  ◦ Beef pancreas / Pork pancreas
  ◦ Human insulin: recombinant DNA origin
Human Insulin:
Do not contain measurable amounts of
 proinsulin or contaminants.
Diminished antibody
Less allergic reactions
Less lipodystrophy
Preferred in gestational diabetes
Insulin preparations:

A.Rapid acting insulin:                   Lispro,
 Aspart and Glulisine
B.Short acting insulin:
    Regular (crystalline)
C. Intermediate acting insulin:
   NPH (isophane) and Lente (insulin zinc)

D. Long acting insulin:
  Protamine—zinc , Ultralente, Detimir and Glargine
Insulin               Duration      Route        Features

Lispro                3 – 5 hrs     I.V or S.C   Onset within 15
                                                 minutes
Rapid acting

Regular               7 – 10 hrs    I.V or S.C common
(crystalline)
Short acting

NPH                   16 – 20 hrs   S.C          NPH can mix
(Neutral protamine                               with regular
hagedorn)
Intermediate acting

Ultralente            24 – 30 hrs   S.C          Basal level
Long acting
The pancreas and glucose homeostasis l4
The pancreas and glucose homeostasis l4
Adverse effects of Insulin

Hypoglycemia
Allergicreactions
Lipodystrophy
Others includes
  ◦ Seizures
  ◦ Coma
Hypoglycemia
Examples of four regimens that provide both prandial and basal insulin
replacement. B = breakfast;L = lunch; S = supper. NPH = neutral protamine
Hagedorn.
Insulin Delivery Systems




Inhaled

Exubera
The pancreas and glucose homeostasis l4
The pancreas and glucose homeostasis l4
The pancreas and glucose homeostasis l4
Oral Anti-diabetic drugs
Mechanisms to reduce blood sugar
1.Stimulation of pancreatic insulin release –
  Sulfonylureas, Meglitinide
2.Reduce the bio-synthesis of glucose in liver –
  Biguanides (Metformin)
3.Increase the sensitivity of target cells to insulin
  -- Thiazolidinediones
4.Retard the absorption of sugars from the GI
  tract – Acarbose, Miglitol
Duration of action of
some oral
hypoglycemic agents.
Major actions of the principal oral antidiabetic drugs used to treat type 2 diabetes
A. Alpha-Glucosidase Inhibitors:
 Acarbose (Glucobay) , Miglitol (Glyset)
 1. They inhibit α-glucosidase which converts
    dietary starch and complex carbohydrates
    into simple sugars
 2. It reduces absorption of glucose after
    meals.
  The main side effects includes flatulence
    and diarrhea.
B. Insulin secretagogues
1.       Sulfonylureas :
        First generation :
     ◦    Acetohexamide
     ◦    Chlorpropamide
     ◦    Tolbutamide
     ◦    Tolazamide
        Second generation : Glipizide, Glyburide
             more potent
             more efficacious
             fewer adverse effects.
        Third generation : Glimiperide
Mechanism of Action:

1)Stimulation of insulin release from the β
 cells of the pancreas by blocking the ATP-
 sensitive K+ channels, resulting in
 depolarization and Ca2+ influx
2)reduction in hepatic glucose production
3)increase in peripheral insulin sensitivity.
Sulfonylureas
The pancreas and glucose homeostasis l4
Dose      Duration
        Sulfonylureas           (mg)        (h)
First Generation
 Tolbutamide (Orinase)        1000-1500     6-8
 Chlorpropamide (Diabinese)    250-375     24-60
 Tolazamide (Tolinase)         250-375     12-24
Second generation
 Glipizide (Glucotrol)           10        10-24

 Glyburide (Micronase)           5         16-24
 (Glibenclamide)
 Third generation                1-2         24
Glimepiride (Amaryl)
Sulfonylureas: Adverse effects :
Hypoglycemia
Cholestatic jaundice
Weight gain
Cross placenta – fetal hypoglycemia.


Chlorpropamide      :
   ◦ It can cause water retention by ↑ release of ADH
     (SIADH)
   ◦ Disulfiram-like reaction with alcohol.
2. Glinides: Repaglinide, Nateglinide
More  rapidly acting insulin enhancers
 and shorter duration than sulfonylurea.
These are insulin secretagogues that act by
 blocking ATP-dependent K+ channels.
This leads to increased insulin secretion by
 pancreatic β-cells.
Hypoglycemia is the common adverse effect.
Less weight gain
Repaglinide, Nateglinide

The   drug has minimal renal excretion thus
 useful in patients with DM and impaired renal
 function. 
It is designed to be taken with each meal to
 stimulate insulin release with meal. If a meal is
 skipped, so is the repaglinide.
C. Insulin sensitizers
          1. Biguanides
          2. Thiazolidinediones

1. Biguanides (Metformin):

 ◦ Inhibits glucose output (gluconeogenesis).
 ◦ It increase the sensitivity of liver and muscle to insulin.
   (increase uptake of glucose)
 ◦ Does not promote insulin secretion.
 ◦ It causes modest weight loss.
Biguanides: Metformin (Glucophage)
 ◦ 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.
2. Thiazolidinediones (glitazones)
Enhance   glucose and lipid metabolism through
  action on Peroxisome Proliferator Activated
  Receptor (PPAR–γ)
Enhance sensitivity to insulin in muscle and fat
  by increasing the GLUT 4 glucose transporters.
E.g. :
Pioglitazone Actos,
Rosiglitazone Avandia: EMA recommended in Sep
 2010 to be suspended from the EU market due to elevated
 cardiovascular risks
Thiazolidinediones:
Beneficial   effects on serum lipid; ↓TG and
 ↑HDL.
Troglitazone(Rezulin), was withdrawn in 1990s
 from the market due to an increased incidence of
 drug-induced hepatitis.

The main side effect of all thiazolidinediones is
 water retention, leading to edema .
Adverse effects of Oral Anti-diabetic drugs
Agent              Mechanism            Site of action        Main advantages     Main side effects

                 Stimulating insulin
                 production by                                 •Effective            •Hypoglycemia
Sulfonylureas    inhibiting the KATP
                                       Pancreatic beta cells
                                                               •Inexpensive          •Weight gain
                 channel


                                                                                     •GI symptoms,
                                                               •May result in mild   including
                 Decreases insulin                             weight loss           diarrhea, nausea,
 Metformin       resistance
                                       Liver
                                                               •Does not cause       abdominal pain
                                                               hypoglycemia          •Lactic acidosis
                                                                                     •Metallic taste

                                                                                     •GI symptoms,
                                                                                     including
                 Reduces intestinal                                                  diarrhea,
  Acarbose       glucose absorption
                                       GI tract                •Low risk
                                                                                     abdominal
                                                                                     cramping,
                                                                                     flatulence

                 Reduce insulin
Thiazolidinedion
                 resistance by         Fat, muscle                                   Hepatoxicity
       es        activating PPAR-γ
NEW CLASSES OF
HYPOGLYCEMICS
A. Incretins
• Glucagon-like peptide-1 (GLP-1)
• Gastric inhibitory peptide (GIP)
• Released from the gut
The pancreas and glucose homeostasis l4
The pancreas and glucose homeostasis l4
•   Function of incretins:
    1. augment glucose-dependent insulin secretion
       after a meal.

    2. They also slow the rate of absorption of nutrients
       into the blood stream by:
              1. reducing gastric emptying
              2. may directly reduce food intake

    3. They inhibit glucagon release from the alpha cells
       of the Islets of Langerhans.
Both  GLP-1 and GIP are rapidly
 inactivated by the enzyme dipeptidyl
 peptidase 4 (DPP-4).




           DPP-4
GIP                         Inactive products
GLP-1
Exenatide
(Byetta) inj




Sitagliptin
 (januvia)




       Dipeptidyl peptidase 4 (DPP-4) inhibitors: SITAGLIPTIN
                                                            ( (januvia
A. Incretin Mimetics:
  •   Exenatide (Byetta)
  •   Liraglutide (Victosa): long duration of action approved in 2010
  • GLP-1 analogs.
  • improves glucose-dependent insulin secretion
  • slows gastric emptying time
  • decreases food intake
  • decreases postprandial glucagon secretion
  • promotes β-cell proliferation.
  • Consequently, weight gain and postprandial
    hyperglycemia are reduced, and HbA1c levels decline.
  • Exenatide is administered subcutaneously.
Exenatide   : Short duration of action.

Use:
as an adjunct to therapy in patients with
 Type 2 diabetes who have failed to achieve
 adequate glycemic control on a sulfonylurea,
 metformin, glitazone, or combination thereof.

Adverse effects:
Nausea, vomiting,   and diarrhea.
Sitagliptin(Januvia) FDA approved Oct 2006
Vildagliptin (Galvus) EU Approved 2008
Saxagliptin (Onglyza) FDA Approved July 2009
Linagliptin (Tradjenta) FDA Approved May 2, 2011




B. Dipeptidyl Peptidase-IV Inhibitors
Sitagliptin (Januvia)
Mechanism of action
• Sitagliptin inhibits the enzyme DPP-IV, which is
  responsible for the inactivation of incretin
  hormones.
• Prolonging the activity of incretin hormones
  results in increased insulin release in response to
  meals and a reduction in inappropriate secretion
  of glucagon.
• Use:
    – as monotherapy or in combination with a
      sulfonylurea, metformin or a glitazone.
Pharmacokinetics and fate

• Well absorbed after oral administration.
• Food does not affect the extent of absorption.
• The majority excreted unchanged in the urine.
• Dosage adjustments are recommended for
  patients with renal dysfunction.

Adverse effects
• Nasopharyngitis and headache.
Synthetic Amylin Analog:
            Pramlintide (SYMLIN):


             Amylin:
37-aa peptide produced by beta cells
 and co-secreted with insulin.
Effects:
  1. Inhibits glucagon secretion
  2. delay gastric emptying
  3. suppress appetite
Pramlintide (SYMLIN):
•indicated as an adjunct to mealtime insulin
 therapy in patients with Type 1 or Type 2
 diabetes.
•Effects:
  - delays gastric emptying
  - decreases postprandial glucagon secretion
  - improves satiety
•Administration of Pramlintide:
  •subcutaneous injection
  •injected immediately prior to meals.


•When pramlintide is initiated, the dose of rapid-
 or short-acting insulin should be decreased by
 50% prior to meals to avoid a risk of severe
 hypoglycemia.



•Adverse effects are mainly gastrointestinal and
 consist of nausea, anorexia, and vomiting.
Agents that increase blood glucose
                  (hyperglycemics)

Glucagon: Uses
A.firstaid in cases of severe hypoglycemia when the
  victim is unconscious or for other reasons cannot
  take glucose orally.
B.treatment of overdose with beta blockers
  ◦ It has positive inotropic action and chronotropic
    action on the heart.
  ◦ It acts by stimulation of glucagon receptors and not
    through beta 1 receptors.
Diazoxide
  Diazoxide is a nondiuretic thiazide that promptly
   increases blood glucose levels by direct inhibition of
   insulin secretion.

  Diazoxide is useful in cases of insulinoma or leucine-
   sensitive hypoglycemia.

  Diazoxide may cause sodium retention, gastrointestinal
   irritation, and changes in circulating white blood cells.

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The pancreas and glucose homeostasis l4

  • 2. Diabetes mellitus DM is characterized by elevated blood sugar levels due to absolute or relative lack of insulin. Type 1 diabetes - β-cell failure at outset ◦ Insulin dependent Type 2 diabetes - Gradual β-cell deterioration ◦ Early stages: Diet and Oral agents ◦ Late-stage: Insulin therapy
  • 5. Glycosylated hemoglobin Hb-A1c Itis used to monitor the plasma glucose concentration over prolonged periods of time (4-6 weeks). Insulin secretion is promoted by: ◦ ↑ blood glucose levels ◦ ↑ amino acids ◦ GI hormones ◦ β-2 agonist: stimulates  glycogenolysis  release of glucagon
  • 8. Beta cells Peripheral tissues
  • 9. Insulin  Insulin is a storage hormone: i. it promotes anabolism ii. inhibits catabolism of carbohydrates, fatty acids and protein.  In the absence of insulin: i. most tissues cannot use glucose ii. fats/proteins are broken down to provide energy.
  • 10. Mechanism of action: Insulin binds to insulin receptors on the plasma membrane and activates tyrosine kinase – primarily in adipose tissue, liver and skeletal muscle.
  • 11. Liver: 1. Insulin increase the storage of glucose as glycogen in the liver. ◦ It inserts the GLUT-2 glucose transport molecule in the cell membrane. 1. It inhibits gluconeogenesis – thus significantly ↓ glucose output by the liver. 2. It decrease the protein catabolism.
  • 13. Muscle : 1. Insulin stimulates the glycogen synthesis and protein synthesis. ◦ Glucose transport into the cells is facilitated by GLUT-4 into the cell membrane. 1. It inhibits the protein catabolism.
  • 14.  Signs and symptoms The classic symptoms of untreated diabetes are loss of weight, polyuria (frequent urination), polydipsia (increased thirst) and polyphagia (increased hunger).[11] Symptoms may develop rapidly (weeks or months) in type 1 diabetes, while they usually develop much more slowly and may be subtle or absent in type 2 diabetes. Prolonged high blood glucose can cause glucose absorption in the lens of the eye, which leads to changes in its shape, resulting in vision changes. Blurred vision is a common complaint leading to a diabetes diagnosis. A number of skin rashes that can occur in diabetes are collectively known as diabetic dermadromes.
  • 15. Diabetic emergencies People (usually with type 1 diabetes) may also present with diabetic ketoacidosis, a state of metabolic dysregulation characterized by the smell of acetone, a rapid, deep breathing known as Kussmaul breathing, nausea, vomiting and abdominal pain, and altered states of consciousness.
  • 16. Complications typically develop after many years (10– 20). damage to blood vessels. Diabetes doubles the risk of cardiovascular disease, ”macrovascular" diseases, (related to atherosclerosis of larger arteries) include ischemic heart disease (angina and myocardial infarction), stroke and peripheral vascular disease.
  • 17. Diabetes also damages the capillaries (causes microangiopathy). Diabetic retinopathy, which affects blood vessel formation in the retina of the eye, can lead to visual symptoms, reduced vision, and potentially blindness. Diabetic nephropathy, the impact of diabetes on the kidneys, can lead to scarring changes in the kidney tissue, loss of small or progressively larger amounts of protein in the urine, and eventually chronic kidney disease requiring dialysis.
  • 18. Diabetic neuropathy is the impact of diabetes on the nervous system, most commonly causing numbness, tingling and pain in the feet and also increasing the risk of skin damage due to altered sensation. Together with vascular disease in the legs, neuropathy contributes to the risk of diabetes-related foot problems (such as diabetic foot ulcers) that can be difficult to treat and occasionally require amputation.
  • 19. Insulin Adipose tissue : 1. Insulin facilitates the storage of triglyceride by: i. activating plasma lipoprotein lipase ii. inhibiting intracellular lipolysis. 2. It increase the glucose uptake by GLUT-4 insertion into the cell membrane.
  • 20. Effect of insulin on glucose uptake and metabolism glycolysis
  • 21. Insulin is a 51 AA peptide Not active orally. Insulin is inactivated by insulinase (insulin transhydrogenase ) found mainly in liver and kidney. Dose reduced in renal insufficiency Sources of Insulin : ◦ Beef pancreas / Pork pancreas ◦ Human insulin: recombinant DNA origin
  • 22. Human Insulin: Do not contain measurable amounts of proinsulin or contaminants. Diminished antibody Less allergic reactions Less lipodystrophy Preferred in gestational diabetes
  • 23. Insulin preparations: A.Rapid acting insulin: Lispro, Aspart and Glulisine B.Short acting insulin: Regular (crystalline) C. Intermediate acting insulin: NPH (isophane) and Lente (insulin zinc) D. Long acting insulin: Protamine—zinc , Ultralente, Detimir and Glargine
  • 24. Insulin Duration Route Features Lispro 3 – 5 hrs I.V or S.C Onset within 15 minutes Rapid acting Regular 7 – 10 hrs I.V or S.C common (crystalline) Short acting NPH 16 – 20 hrs S.C NPH can mix (Neutral protamine with regular hagedorn) Intermediate acting Ultralente 24 – 30 hrs S.C Basal level Long acting
  • 27. Adverse effects of Insulin Hypoglycemia Allergicreactions Lipodystrophy Others includes ◦ Seizures ◦ Coma
  • 29. Examples of four regimens that provide both prandial and basal insulin replacement. B = breakfast;L = lunch; S = supper. NPH = neutral protamine Hagedorn.
  • 34. Oral Anti-diabetic drugs Mechanisms to reduce blood sugar 1.Stimulation of pancreatic insulin release – Sulfonylureas, Meglitinide 2.Reduce the bio-synthesis of glucose in liver – Biguanides (Metformin) 3.Increase the sensitivity of target cells to insulin -- Thiazolidinediones 4.Retard the absorption of sugars from the GI tract – Acarbose, Miglitol
  • 35. Duration of action of some oral hypoglycemic agents.
  • 36. Major actions of the principal oral antidiabetic drugs used to treat type 2 diabetes
  • 37. A. Alpha-Glucosidase Inhibitors: Acarbose (Glucobay) , Miglitol (Glyset) 1. They inhibit α-glucosidase which converts dietary starch and complex carbohydrates into simple sugars 2. It reduces absorption of glucose after meals.  The main side effects includes flatulence and diarrhea.
  • 38. B. Insulin secretagogues 1. Sulfonylureas :  First generation : ◦ Acetohexamide ◦ Chlorpropamide ◦ Tolbutamide ◦ Tolazamide  Second generation : Glipizide, Glyburide  more potent  more efficacious  fewer adverse effects.  Third generation : Glimiperide
  • 39. Mechanism of Action: 1)Stimulation of insulin release from the β cells of the pancreas by blocking the ATP- sensitive K+ channels, resulting in depolarization and Ca2+ influx 2)reduction in hepatic glucose production 3)increase in peripheral insulin sensitivity.
  • 42. Dose Duration Sulfonylureas (mg) (h) First Generation Tolbutamide (Orinase) 1000-1500 6-8 Chlorpropamide (Diabinese) 250-375 24-60 Tolazamide (Tolinase) 250-375 12-24 Second generation Glipizide (Glucotrol) 10 10-24 Glyburide (Micronase) 5 16-24 (Glibenclamide) Third generation 1-2 24 Glimepiride (Amaryl)
  • 43. Sulfonylureas: Adverse effects : Hypoglycemia Cholestatic jaundice Weight gain Cross placenta – fetal hypoglycemia. Chlorpropamide : ◦ It can cause water retention by ↑ release of ADH (SIADH) ◦ Disulfiram-like reaction with alcohol.
  • 44. 2. Glinides: Repaglinide, Nateglinide More rapidly acting insulin enhancers and shorter duration than sulfonylurea. These are insulin secretagogues that act by blocking ATP-dependent K+ channels. This leads to increased insulin secretion by pancreatic β-cells. Hypoglycemia is the common adverse effect. Less weight gain
  • 45. Repaglinide, Nateglinide The drug has minimal renal excretion thus useful in patients with DM and impaired renal function.  It is designed to be taken with each meal to stimulate insulin release with meal. If a meal is skipped, so is the repaglinide.
  • 46. C. Insulin sensitizers 1. Biguanides 2. Thiazolidinediones 1. Biguanides (Metformin): ◦ Inhibits glucose output (gluconeogenesis). ◦ It increase the sensitivity of liver and muscle to insulin. (increase uptake of glucose) ◦ Does not promote insulin secretion. ◦ It causes modest weight loss.
  • 47. Biguanides: Metformin (Glucophage) ◦ 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.
  • 48. 2. Thiazolidinediones (glitazones) Enhance glucose and lipid metabolism through action on Peroxisome Proliferator Activated Receptor (PPAR–γ) Enhance sensitivity to insulin in muscle and fat by increasing the GLUT 4 glucose transporters. E.g. : Pioglitazone Actos, Rosiglitazone Avandia: EMA recommended in Sep 2010 to be suspended from the EU market due to elevated cardiovascular risks
  • 49. Thiazolidinediones: Beneficial effects on serum lipid; ↓TG and ↑HDL. Troglitazone(Rezulin), was withdrawn in 1990s from the market due to an increased incidence of drug-induced hepatitis. The main side effect of all thiazolidinediones is water retention, leading to edema .
  • 50. Adverse effects of Oral Anti-diabetic drugs
  • 51. Agent Mechanism Site of action Main advantages Main side effects Stimulating insulin production by •Effective •Hypoglycemia Sulfonylureas inhibiting the KATP Pancreatic beta cells •Inexpensive •Weight gain channel •GI symptoms, •May result in mild including Decreases insulin weight loss diarrhea, nausea, Metformin resistance Liver •Does not cause abdominal pain hypoglycemia •Lactic acidosis •Metallic taste •GI symptoms, including Reduces intestinal diarrhea, Acarbose glucose absorption GI tract •Low risk abdominal cramping, flatulence Reduce insulin Thiazolidinedion resistance by Fat, muscle Hepatoxicity es activating PPAR-γ
  • 53. A. Incretins • Glucagon-like peptide-1 (GLP-1) • Gastric inhibitory peptide (GIP) • Released from the gut
  • 56. Function of incretins: 1. augment glucose-dependent insulin secretion after a meal. 2. They also slow the rate of absorption of nutrients into the blood stream by: 1. reducing gastric emptying 2. may directly reduce food intake 3. They inhibit glucagon release from the alpha cells of the Islets of Langerhans.
  • 57. Both GLP-1 and GIP are rapidly inactivated by the enzyme dipeptidyl peptidase 4 (DPP-4). DPP-4 GIP Inactive products GLP-1
  • 58. Exenatide (Byetta) inj Sitagliptin (januvia) Dipeptidyl peptidase 4 (DPP-4) inhibitors: SITAGLIPTIN ( (januvia
  • 59. A. Incretin Mimetics: • Exenatide (Byetta) • Liraglutide (Victosa): long duration of action approved in 2010 • GLP-1 analogs. • improves glucose-dependent insulin secretion • slows gastric emptying time • decreases food intake • decreases postprandial glucagon secretion • promotes β-cell proliferation. • Consequently, weight gain and postprandial hyperglycemia are reduced, and HbA1c levels decline. • Exenatide is administered subcutaneously.
  • 60. Exenatide : Short duration of action. Use: as an adjunct to therapy in patients with Type 2 diabetes who have failed to achieve adequate glycemic control on a sulfonylurea, metformin, glitazone, or combination thereof. Adverse effects: Nausea, vomiting, and diarrhea.
  • 61. Sitagliptin(Januvia) FDA approved Oct 2006 Vildagliptin (Galvus) EU Approved 2008 Saxagliptin (Onglyza) FDA Approved July 2009 Linagliptin (Tradjenta) FDA Approved May 2, 2011 B. Dipeptidyl Peptidase-IV Inhibitors
  • 62. Sitagliptin (Januvia) Mechanism of action • Sitagliptin inhibits the enzyme DPP-IV, which is responsible for the inactivation of incretin hormones. • Prolonging the activity of incretin hormones results in increased insulin release in response to meals and a reduction in inappropriate secretion of glucagon. • Use: – as monotherapy or in combination with a sulfonylurea, metformin or a glitazone.
  • 63. Pharmacokinetics and fate • Well absorbed after oral administration. • Food does not affect the extent of absorption. • The majority excreted unchanged in the urine. • Dosage adjustments are recommended for patients with renal dysfunction. Adverse effects • Nasopharyngitis and headache.
  • 64. Synthetic Amylin Analog: Pramlintide (SYMLIN): Amylin: 37-aa peptide produced by beta cells and co-secreted with insulin. Effects: 1. Inhibits glucagon secretion 2. delay gastric emptying 3. suppress appetite
  • 65. Pramlintide (SYMLIN): •indicated as an adjunct to mealtime insulin therapy in patients with Type 1 or Type 2 diabetes. •Effects: - delays gastric emptying - decreases postprandial glucagon secretion - improves satiety
  • 66. •Administration of Pramlintide: •subcutaneous injection •injected immediately prior to meals. •When pramlintide is initiated, the dose of rapid- or short-acting insulin should be decreased by 50% prior to meals to avoid a risk of severe hypoglycemia. •Adverse effects are mainly gastrointestinal and consist of nausea, anorexia, and vomiting.
  • 67. Agents that increase blood glucose (hyperglycemics) Glucagon: Uses A.firstaid in cases of severe hypoglycemia when the victim is unconscious or for other reasons cannot take glucose orally. B.treatment of overdose with beta blockers ◦ It has positive inotropic action and chronotropic action on the heart. ◦ It acts by stimulation of glucagon receptors and not through beta 1 receptors.
  • 68. Diazoxide  Diazoxide is a nondiuretic thiazide that promptly increases blood glucose levels by direct inhibition of insulin secretion.  Diazoxide is useful in cases of insulinoma or leucine- sensitive hypoglycemia.  Diazoxide may cause sodium retention, gastrointestinal irritation, and changes in circulating white blood cells.