Transcript PPT
May 20
Diabetes Mellitus
Munir Gharaibeh, MD, PhD, MHPE Faculty of Medicine The Jordan University April 2014
Munir Gharaibeh, MD, PhD, MHPE 1
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Diabetes Mellitus
A disease characterized by high blood sugar level?
A disease characterized by insulin deficiency?
A metabolic disorder manifested by abnormalities in CHO, lipid and protein metabolism
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Diabetes Mellitus
Diabetes is a major cause of heart disease and stroke
Diabetes is the leading cause of kidney failure, nontraumatic lower-limb amputations, and new cases of blindness among adults in the United States
Diabetes is the seventh leading cause of death in the United States
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Type I; Juvenile-onset; IDDM
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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 kids less than 6 months.
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Type I; Juvenile-onset; IDDM
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Patients have little or no pancreatic function Often present with ketoacidosis Characterized by downhill course-severe type of DM (mortality is high) Easy to diagnose (pts usually present with weight loss; easy fatigability; polyuria; polydipsia; polyphagia … )
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Type I; Juvenile-onset; IDDM
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Type I DM in most cases is associated with HLA types (histocompatibility antigens) and presence of β-islet cell antibodies suggesting an autoimmune mediated destruction of insulin producing cells and hence to a near total loss of endogenous insulin production
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Insulin lack could be idiopathic
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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 Hx (?genetic background).
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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)
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Clinical Picture of DM
Early manifestations:
Polyurea, Polydipsia, Polyphagia, Ketoacidosis (type I).
Late manifestations or complications:
Atherosclerosis & IHD, Retinopathy, Nephropathy , Neuropathy
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Diagnosis of DM
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Clinical manifestations - Lab. Tests: Random blood sugar (RBS) Fasting blood sugar Glycosylated hemoglobin Glucose tolerance test
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Goals of DM Treatment
Ensure good patient-clinic relationship.
Control symptoms.
Prevent acute metabolic crisis of KA & hypoglycemia.
Maintain normal growth & BW.
Encourage self-reliance & self-care.
Eliminate risk factors: Smoking, ↑ BP, ↑ lipids …
11 May 20 Munir Gharaibeh, MD, PhD, MHPE
Goals of DM Treatment
Prevent psychological complications: Accept restrictions on life Diet control Monitoring blood glucose & insulin adjustment Know manifestations of hypoglycemia & how to avoid them.
Early treatment of complications: Photocoagulation, foot care advices...
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Management of DM
Type I: Diet + Insulin therapy Type II: Diet + exercise
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Oral hypoglycemic agents Insulin
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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
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Insulin Protein; A (21 aa) & B (30 aa) chains; disulfied bonds
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Secretion of Insulin
Ca ++ dependent [blood glucose] is the major regulator
Factors/drugs ↑ release: Glucose; AAs; FAs; GH; glucagon; ACTH; sulfonylureas; β-adrenergics, cholinergic drugs …
Factors/drugs ↓ release: α-adrenergics; anticholinergics; phenytoin; alloxan; streptozotocin (streptozocin)
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Mechanism of Action of Insulin
Insulin binds to its receptor leading to phosphorylation of insulin-receptor complex which in turn starts many protein kinases activation cascades . These include: translocation of Glu transporter-4 to the plasma membrane and influx of glucose, glycogen synthesis, glycolysis and fatty acid synthesis.
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Effects of Insulin
↑ glucose uptake or transport → muscles & adipocytes ↑ glucose oxidation by muscles ↓ hepatic gluconeogenesis ↑ hepatic glycogen synthesis and storage; ↓ glycogenolysis ↑ AA uptake and protein synthesis by muscles and liver ↓ lipolysis ↓ ketogenesis
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Insulin Preparations Natural:
Bovine Porcine.
Human: limited supply, short t 1/2 with stability & problems
Biosynthetic:
rHI
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Insulin Preparations
Potency: Human > porcine > bovine Allergy: - Bovine > porcine > human(proinsulin is a major contaminant).
Insulins are classified according to duration of action (DOA)
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Factors Affecting Insulin Absorption Site of injection: abdomen > arm > buttocks > 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.
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Insulin Preparations
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** Ultra-rapid onset; very short acting: Insulin Lispro Insulin Aspart Insulin Glulisine O (hr) P (hr) DOA (hr) 0.25-0.5 0.5-1 3-4
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** Rapid onset & short acting: Crystalline zinc 0.3-0.7 2-4 5-8 (Regular; Soluble) Insulin zinc prompt (Semilente)
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Insulin Preparations
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** Intermediate onset & action: Insulin zinc suspension 1-2 6-12 18-24 (Lente) Isophane insulin suspension (NPH; Humulin)
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** Slow onset & action: Protamine zinc suspension 4-6 14-20 24-36 Extended insulin zinc suspension (Ultralente)
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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
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Insulin Preparations
Advantages of peakless insulins over intermediate-acting insulins: - Constant circulating insulin over 24hr with no pronounced peak.
- Reduced risk of hypoglycemia (esp. nocturnal hypoglycemia).
- Clear solution that does not require resuspension before administration.
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All insulin preparations are mainly given S.C; except regular insulin, insulin Glulisine & insulin Aspart , which can also be given IV
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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
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Side Effects of Insulin Therapy
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Hypoglycemia; ↑ sympathetic activity Lipodystrophy Allergy Induration
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Oral Hypoglycemic Agents
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Oral Hypoglycemic Agents
Biguanides Metformin Metformin is only effective in type II DM (effects require insulin) ↓ CHO absorption ↓ hepatic gluconeogenesis; ↑ glycolysis ↓ glucagon release ↑ peripheral utilization of glucose
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Biguanides
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Side effects: N & V, metallic taste Abdominal pain and diarrhea Hypoglycemia is rare.
Lactic acidosis.
↓ Vitamin B 12 absorption.
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First Generation Tolbutamide
Sulfonylureas
t 1/2 DOA 7 6-12 Chlorpropamide Tolazamide Acetohexamide 34 24-72 7 12-16 5 12-18
37 May 20 Munir Gharaibeh, MD, PhD, MHPE
Sulfonylureas
Second Generation t 1/2 DOA Glyburide (Glibenclamide) 4 20-24 Glipizide 3 14-16 Gliclazide Glimeperide 8 10-15 5 18-22
38 May 20 Munir Gharaibeh, MD, PhD, MHPE
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Actions of Sulfonylureas
↑ insulin release (major MOA) (Receptor-mediated effect) ↑ no. of β-cells, ↑ no. of insulin receptors ↑ peripheral cells sensitivity to insulin effect ↑ insulin binding to its receptors ↑ insulin affinity to its receptors ↓ hepatic gluconeogenesis ↓ glucagon release, ↑ somatostatin release …
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Mechanism of Action of Sulfonylureas Drug binds 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.
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K ATP Channel Structure and Function glucose ATP-sensitive K + Channel (K ATP Channel) Sulfonylurea Receptor Inwardly Rectifying K + Channel Voltage-dependent Ca 2+ Channel Membrane Depolarization
NBF
K + ATP
NBF
glucose metabolism insulin secretion NBF Nucleotide Binding Fold = site of ATP/ADP binding Ca 2+ Influx Four copies of each subunit combine to form an active K ATP channel
May 20 http://www.musc.edu/~rosenzsa Munir Gharaibeh, MD, PhD, MHPE 41
Sulfonylureas
Sulfonylureas differ in potency, bioavailability, DOA, tolerance, extent of protein binding and metabolic fate
Drug-drug interactions (many): Propranolol, sulfa drugs, oral anticoagulants, aspirin, ↑ effects of sulfonylureas
Clinical uses: DM Nocturnal enuresis (Glyburide → ↑ ADH release)
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Side Effects of Sulfonylureas
Hypoglycemia, like insulin.
N & V, dizziness.
Allergy.
Agranulocytosis.
Hepatic dysfunction.
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α-glucosidase inhibitors
Acarbose Miglitol (more potent) Effective in type II DM ↓ CHO absorption Inhibit α-glucosidase brush border of intestine responsible for breakdown of CHO, and hence ↓ glucose absorption.
, an enzyme in the ↓ fasting and postprandial hyperglycemia.
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α-glucosidase inhibitors
α-glucosidase inhibitors also ↓ insulin secretion following administration, thus sparing β-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.
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Prandial Glucose Regulators
Repaglinide Nateglinide Mitiglinide… ↑ insulin release (similar action to sulfonylureas).
Taken before meals (every meal).
Could be taken with metformin or insulin.
Hypoglycemia is infrequent.
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Thiazolidinediones (TZD
’
s)
Rosiglitazone (? withdrawn) Pioglitazone (has shorter t 1/2 ) Troglitazone resistance.
... Used in NIDDM patients who have insulin Peroxisome Proliferator-Activated Receptors (PPAR) agonists PPAR ’ s are members of the superfamily of ligand activated transcription factors located in adipose tissue, skeletal muscle and large intestine
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Thiazolidinediones (TZD
effect ↓ glucose exit or output from the liver ↓insulin resistance insulin resistance ’
s)
↑ sensitivity of peripheral tissues to insulin Good for patients with ↑ insulin levels, which are believed to be responsible for ↑ B.P,↑ lipids and atherosclerosis in patients with
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gut.
Incretin Hormones
2 polypeptides which ↑ glucose absorption by 1. Glucagon-like peptide-1 (GLP-1).
Produced by the L cells in ileum and colon.
↑ insulin release and ↓ glucagon release following meals.
↓ gastric emptying & leads to induction of satiety.
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Glucagon-like peptide-1 (GLP-1)
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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 β-cells Both GLP & GIP are metabolized by the enzyme dipeptidyl peptidase-4 (DPP-4) endothelial cells which is present in gut, liver, kidneys, lymphocytes and
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Incretin Hormones
In normal people In type II D.M (reduced) incretin effect oral Insulin glucose Blood I.V
Level Time (min) Time (min)
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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 infrequent
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Incretin Hormones
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.
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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.
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Other Drugs
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Somatostatin
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In low doses → ↓ glucagon release Drugs Under Evaluation: ACEI’s; ARB’s; Statins.
Pancreatic transplantation and gene therapy
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Drugs ↓ blood glucose levels
β-blockers Salicylates, indomethacin, naproxin Alcohol.
Sulfonamides Clofibrate Anabolic steroids.
Lithium Ca ++ Aampicillin Bromocriptine …
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Drugs ↑ blood glucose levels
β-blockers.
Thiazides and loop diuretics.
Glucocorticoids Oral contraceptive drugs Ca ++ channel blockers Phenytoin.
Morphine Heparin Nicotine Clonidine Diazoxide H 2 -receptor blockers
Munir Gharaibeh, MD, PhD, MHPE 59
Goals of DM Treatment
Ensure good patient-clinic relationship.
Control symptoms.
Prevent acute metabolic crisis of KA & hypoglycemia.
Maintain normal growth & BW.
Encourage self-reliance & self-care.
Eliminate risk factors: Smoking, ↑ BP, ↑ lipids …
60 May 20 Munir Gharaibeh, MD, PhD, MHPE
Goals of DM Treatment
Prevent psychological complications: Accept restrictions on life Diet control Monitoring blood glucose & insulin adjustment Know manifestations of hypoglycemia & how to avoid them.
Early treatment of complications: Photocoagulation, foot care advices...
61 May 20 Munir Gharaibeh, MD, PhD, MHPE