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Diabetes Mellitus

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Diabetes Mellitus Munir Gharaibeh, MD, PhD, MHPE Faculty of Medicine The Jordan University August 2015 * Munir Gharaibeh, MD, PhD, MHPE * Oral Hypoglycemic Agents ... – PowerPoint PPT presentation

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Title: Diabetes Mellitus


1
Diabetes Mellitus
  • Munir Gharaibeh, MD, PhD, MHPE
  • Faculty of Medicine
  • The Jordan University
  • August 2015

2
Diabetes Mellitus
  • Diabetes is a major cause of heart disease and
    stroke
  • Diabetes is a leading cause of renal failure,
    nontraumatic lower-limb amputations, and
    blindness.
  • Diabetes is the seventh leading cause of death in
    the United States

3
Type I Juvenile-onset IDDM
  • 10-20 of diabetics
  • Most commonly occurs in childhood or adolescence
    but may occur at any age
  • Mainly affects children at an age 10-14, not
    reported in children less than 6 months of age.

4
Type I Juvenile-onset IDDM
  • Patients have little or no pancreatic function
  • Often present with ketoacidosis
  • Characterized by downhill course-severe type of
    DM with high mortality.
  • Easy to diagnose ( severe weight loss easy
    fatigability polyuria polydipsia polyphagia
    etc)

5
Type I Juvenile-onset IDDM
  • Usually associated with HLA types
    histocompatibility antigens and presence of
    ß-islet cell antibodies suggesting an
    autoimmune-mediated destruction of insulin
    producing cells leading to a near total loss of
    endogenous insulin production.
  • Insulin lack could be idiopathic

6
Type II Maturity or Adult-onset IIDM
  • Represents 80-90 of diabetics
  • Usually discovered accidentally after age
  • 30-40 yrs
  • Most patients are obese .
  • More common in females as compared to males.
  • Patients have strong family history of DM
    (?genetic background).

7
Type II Maturity or Adult-onset IIDM
  • Most cases have mild polyuria and fatigue.
  • Ketoacidosis is rare, unless in certain
    circumstances of unusual stress.
  • Insulin blood levels could be low, normal or
    high.
  • Insulin resistance is common (pre-receptor
    receptor post-receptor mechanisms)

8
Clinical Picture of DM
  • Early manifestations
  • Polyurea, Polydipsia, Polyphagia, Ketoacidosis
    (type I).
  • Late manifestations or complications
  • Atherosclerosis, IHD, Retinopathy, Nephropathy ,
    Neuropathy

9
Diagnosis of DM
  • - Clinical manifestations
  • - Laboratory Tests
  • Random blood sugar (RBS)
  • Fasting blood sugar
  • Glycosylated hemoglobin
  • Glucose tolerance test

10
Goals of DM Treatment
  • Ensure good patient-clinic relationship.
  • Control symptoms.
  • Prevent acute metabolic crisis of ketoacidosis
    and hypoglycemia.
  • Maintain normal growth and body weight.
  • Encourage self-reliance and self-care.
  • Eliminate risk factors Smoking, BP, lipids.

11
Goals of DM Treatment
  • Prevent psychological complications
  • Accept restrictions on life style.
  • Diet control
  • Monitoring blood glucose and insulin adjustment
  • Know manifestations of hypoglycemia how to
    avoid them.
  • Early treatment of complications
    Photocoagulation, foot care advices...

12
Management of DM
  • -Type I
  • Diet
  • Insulin therapy
  • -Type II
  • Diet exercise
  • Oral hypoglycemic agents
  • Insulin

13
Biosynthesis of Insulin
  • RER
    Golgi Insulin
  • Preproinsulin Proinsulin

  • C-peptide
  • Proinsulin has slight insulin-like activity (1/10
    the potency of insulin)
  • C-peptide is devoid of any insulin-like activity

14
  • Insulin is a protein composed of two chains.
  • A (21 a.a) and B (30 a.a) combined through
    disulfied bonds

15
Secretion of Insulin
  • Ca dependent
  • Blood glucoselevel is the major regulator.
  • Factors/drugs ? release
  • Glucose AAs FAs GH glucagon ACTH
    sulfonylureas ß-adrenergics, cholinergic drugs
  • Factors/drugs ? release
  • a-adrenergics anticholinergics phenytoin
    alloxan streptozocin.

16
  • Mechanism of Action of Insulin
  • Insulin binds to its receptor leading to
    phosphorylation of insulin-receptor complex which
    in turn starts many protein -kinase activation
    cascades . These include translocation of Glu
    transporter-4 to the plasma membrane and influx
    of glucose, glycogen synthesis, glycolysis and
    fatty acid synthesis.

17
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18
Effects of Insulin
  • ? Glucose uptake or transport into muscles and
    adipocytes.
  • ? Glucose oxidation by muscles.
  • ? Hepatic gluconeogenesis.
  • ? Hepatic glycogen synthesis and storage.
  • ? Glycogenolysis.
  • ? AA uptake and protein synthesis by muscles and
    liver.
  • ? Lipolysis.
  • ? Ketogenesis.

19
Insulin Preparations
  • Natural
  • Bovine
  • Porcine.
  • Human
  • limited supply, short t1/2 and has
    problems of poor stability.
  • Biosynthetic rHI

20
Insulin Preparations
  • - Potency
  • Human gt porcine gt bovine
  • Allergy
  • - Bovine gt porcine gt human(proinsulin is a major
    contaminant).
  • Insulins are classified according to duration of
    action (DOA)

21
Factors Affecting Insulin Absorption
  • - Site of injection
  • abdomen gt arm gt buttocks gt thigh.
  • - Exercise increases blood flow at site.
  • - Depth of injection.
  • - Concentration and dose of insulin.
  • - Addition of protamine or isophane to insulin
    preparations delays absorption and hence
    duration of action.

22
Insulin Preparations
  • Ultra-rapid onset very short acting

  • O (hr) P (hr) DOA (hr)
  • Insulin Lispro 0.25-0.5
    0.5-1 3-4
  • Insulin Aspart
  • Insulin Glulisine
  • Rapid onset and short acting
  • Crystalline zinc 0.3-0.7
    2-4 5-8
  • (Regular Soluble)
  • Insulin zinc prompt
  • (Semilente)

23
Insulin Preparations
  • Intermediate onset and action
  • Insulin zinc suspension 1-2
    6-12 18-24
  • (Lente)
  • Isophane insulin suspension
  • (NPH Humulin)
  • Slow onset and action
  • Protamine zinc suspension 4-6
    14-20 24-36
  • Extended insulin zinc suspension
  • (Ultralente)

24
Insulin Preparations
  • Peakless Insulins
  • Insulin Glargine 1-2
    - 24-36
  • Insulin Detemir
  • Mixed insulins
  • Int. short 0.5-1
    3-8 20-24
  • Int. long 2-4
    4-16 22-24

25
Insulin Preparations
  • Advantages of peakless insulins over
    intermediate-acting insulins
  • - Constant circulating insulin over 24hr with no
    pronounced peak.
  • - Reduced risk of hypoglycemia (especially
    nocturnal hypoglycemia).
  • - Clear solution that does not require
  • resuspension before administration.

26
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28
All insulin preparations are mainly given S.C
except regular insulin, insulin Glulisine
insulin Aspart , which can also be given IV
29
Methods of insulin administration
  • - Insulin Syringes
  • - Pre-filled insulin pens
  • - Insulin Jet injectors
  • - External insulin pump
  • Methods under clinical trials
  • - Oral tablets
  • - Inhaled aerosol
  • Intranasal,
  • Transdermal
  • - Buccal spray

30
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32
Side Effects of Insulin Therapy
  • Hypoglycemia manifested as symptoms of
    sympathetic ove ractivity.
  • Lipodystrophy
  • Allergy
  • Induration

33
Oral Hypoglycemic Agents
34
Oral Hypoglycemic AgentsBiguanides
  • Metformin
  • Only effective in type II DM (effects require
    insulin).
  • ? CHO absorption.
  • ? Hepatic gluconeogenesis ? glycolysis.
  • ? Glucagon release.
  • ? Peripheral utilization of glucose.

35
Biguanides
  • Side effects
  • Nausea and vomiting, metallic taste.
  • Abdominal pain and diarrhea.
  • Hypoglycemia is rare.
  • Lactic acidosis.
  • ? Vitamin B12 absorption.

36
Sulfonylureas
  • First Generation t1/2
    DOA
  • Tolbutamide 7
    6-12
  • Chlorpropamide 34
    24-72
  • Tolazamide 7
    12-16
  • Acetohexamide 5
    12-18

37
Sulfonylureas
  • Second Generation t1/2
    DOA
  • Glyburide (Glibenclamide) 4
    20-24
  • Glipizide 3
    14-16
  • Gliclazide 8
    10-15
  • Glimeperide 5
    18-22

38
Actions of Sulfonylureas
  • ? Insulin release (major MOA) (Receptor-mediated
    effect)
  • ? Number of ß-cells and insulin receptors.
  • ? Peripheral cells sensitivity to insulin effect.
  • ? Insulin binding to its receptors.
  • ? Insulin affinity to its receptors.
  • ? Hepatic gluconeogenesis.
  • ? Glucagon release.
  • ? Somatostatin release.

39
Mechanism of Action of Sulfonylureas
  • Bind to receptors linked to ATP-ase sensitive K
    ion channel causing depolarization and opening
    of voltage dependent Ca channels and influx
    of Ca .
  • Ca binds to Calmodulin which activates kinases
    that cause exocytosis of insulin from the
    secretory granules.
  • Beta cells sense glucose more efficiently,
    producing more insulin.

40
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41
Sulfonylureas
  • Sulfonylureas differ in potency, bioavailability,
    duration, tolerance, extent of protein binding,
    and metabolic fate.
  • Sulfonylureas have many interactions
  • Propranolol, sulfa drugs, oral anticoagulants,
    aspirin, ? effects of sulfonylureas
  • Clinical uses
  • DM
  • Nocturnal enuresis (Glyburide ? ? ADH release)

42
Side Effects of Sulfonylureas
  • Hypoglycemia, like insulin.
  • Nausea, vomiting, dizziness.
  • Allergy, due to sulfa moiety.
  • Agranulocytosis.
  • Hepatic dysfunction.

43
a-Glucosidase Inhibitors
  • Acarbose
  • Miglitol (more potent)
  • Effective in type II DM
  • ? CHO absorption
  • Inhibit a-glucosidase , an enzyme in the brush
    border of intestine responsible for breakdown of
    CHO, and hence ? glucose absorption.
  • ? Fasting and postprandial hyperglycemia.

44
a-Glucosidase Inhibitors
  • ? Insulin secretion, thus sparing ß-cells.
  • Reduce incidence and risk of atherosclerosis in
    diabetics
  • Taken before or with meals.
  • Could be given with insulin and sulfonylureas.
  • Cause abdominal pain and diarrhea.

45
Prandial Glucose Regulators
  • Repaglinide
  • Nateglinide
  • Mitiglinide
  • ? Insulin release (similar action to
    sulfonylureas).
  • Taken before meals.
  • Could be taken with metformin or insulin.
  • Hypoglycemia is infrequent.

46
Thiazolidinediones (TZDs)
  • Rosiglitazone (withdrawn)
  • Pioglitazone (has shorter t1/2)
  • Troglitazone
  • Used in NIDDM patients who have insulin
    resistance.
  • Peroxisome Proliferator-Activated Receptors
    (PPAR) agonists.
  • PPARs are members of the superfamily of
    ligand-activated transcription factors located in
    adipose tissue, skeletal muscle and large
    intestine.

47
Thiazolidinediones (TZDs)
  • ? Sensitivity of peripheral tissues to insulin
    effect.
  • ? Glucose exit or output from the liver.
  • ?insulin resistance.
  • Good for patients with ? insulin levels, which
    are also believed to be responsible for ? B.P,?
    lipids and atherosclerosis in patients with
    insulin resistance.

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49
Incretin Hormones
  • 2 polypeptides which ? glucose absorption by gut.
  • 1. Glucagon-like peptide-1 (GLP-1).
  • Produced by the L cells in ileum and colon
  • A.? Insulin release and ? glucagon release
    following meals.
  • B. ? Gastric emptying and induction of satiety.

50
Glucagon-like peptide-1 (GLP-1)
51
Incretin Hormones
  • 2. Glucose-dependent insulinotropic polypeptide
    (GIP)
  • Produced by the K cells in the proximal gut
    (duodenum proximal jejunum)
  • Stimulates glucose-dependent insulin release from
    ß-cells.
  • Both GLP GIP are metabolized by the enzyme
    dipeptidyl peptidase-4 (DPP-4) which is present
    in gut, liver, kidneys, lymphocytes and
    endothelial cells.

52
Incretin Hormones
  • Normal people
    Type 2 D.M patients

  • Incretin effect
  • Oral
  • Insulin glucose
  • Blood I.V
  • Level
  • Time (min)
    Time (min)

53
Incretin Hormones Inhibitors
  • Sitagliptin
  • Gemigliptin
  • Linagliptin
  • Orally effective selective DPP-4 inhibitors
  • ? blood levels of GLP-1, GIP, insulin, and
    C-peptide and ? glucagon blood levels.
  • A daily oral dose reduces high blood glucose and
    HbA1c levels.
  • Could be taken with metformin or sulfonylureas
  • Hypoglycemia is not common.

54
Incretin Hormones Agonists
  • Exenatide
  • Liraglutide
  • Synthetic analogs to GLP-1
  • ? insulin and ? glucagon blood levels
  • Considered as an adjunct therapy to metformin or
    sulfonylureas in patients with type 2 DM who
    still have suboptimal glycemic control.
  • Given S.C, 60 min before meal.
  • Hypoglycemia is infrequent

55
Aldose Reductase (AR) Inhibitors
  • Epalrestat
  • Ranirestat
  • Fidarestat
  • AR
    AR
  • Glucose Fructose
    Sorbitol
  • Sorbitol has been implicated in the pathogenesis
    of retinopathy, neuropathy and nephropathy
  • AR inhibitors proved to improve diabetic
    polyneuropathy.
  • Orally effective.

56
Other Drugs
  • Somatostatin
  • In low doses ? ? glucagon release
  • Drugs Under Evaluation
  • ACEIs ARBs Statins.
  • Pancreatic transplantation and gene therapy

57
Drugs ? Glucose Levels
  • ß-blockers
  • Salicylates, indomethacin, naproxin
  • Alcohol.
  • Sulfonamides
  • Clofibrate
  • Anabolic steroids.
  • Lithium
  • Ca
  • Ampicillin
  • Bromocriptine.

58
Drugs ? Glucose Levels
  • ß-agonists.
  • Thiazides and loop diuretics.
  • Glucocorticoids
  • Oral contraceptive drugs
  • Cachannel blockers
  • Phenytoin.
  • Morphine
  • Heparin
  • Nicotine
  • Clonidine
  • Diazoxide
  • H2-receptor blockers
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