Insulin and oral hypoglycemic drugs

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• Insulin and oral hypoglycemic drugs

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Islet of Langerhans Alpha cell 20,
glucagon Beta cell 75, insulin Delta cell 5,
somatostatin D1 cell VIP PP cell pancreatic
polypeptide
Endogenous insulin is secreted from ? cells in
the pancreas
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Glucose metabolism and the regulation by insulin
and glucogan
Diabetes mellitus Insulin ? or its responses ? ?
blood glucose ? ? Acute or chronic symptoms
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Diabetes Mellitus

• A group of diseases characterized by high levels
  of blood glucose resulting from defects in
  insulin production, insulin action, or both
• 100 million people worldwide
• 85-90 cases are Type II

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CLASSIFICATION

• TYPE 1 (IDDM,10)
• Deficiency of insulin secretion
• Genetic predisposition and possible links to
  viral infections and environmental factors
• Possible autoimmune process with destruction of
  beta pancreatic cells
• Require insulin supplementation, prone to develop
  DKA (?????)

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CLASSIFICATION

• TYPE 2
• Resistance to action of insulin on target organs
• Decrease in insulin production
• Increased risk with obesity high fat, high
  caloric diets
• Stronger genetic predisposition
• Variety of initial presentations HHNKS
  (????????????), nephropathy, retinopathy,
  neuropathies
• Disease can be delayed or prevented with life
  style changes

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Natural History of Type 2 Diabetes
Obesity IGT Diabetes
Uncontrolled hyperglycemia
350
Post-meal Glucose
300
250
Fasting Glucose
Glucose (mg/dL)
200
150
100
50
250
Insulin Resistance
200
Relative Function ()
150
100
Insulin Level
50
Beta-cell failure
0
-10
-5
0
5
10
15
20
25
30
Years of Diabetes
IGT impaired glucose tolerance
Adapted from International Diabetes Center
(IDC) Minneapolis, Minnesota
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CLASSIFICATION

• SECONDARY CAUSES
• Exocrine pancreas disease pancreatitis
• Genetic syndromes Downs, Turners
• Infections CMV, Congenital rubella
• Drugs Glucocorticoids, Dilantin, beta agonists
• Endocrinopathies Cushing's, Acromegaly

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Classification

• Gestational
• Presents only during pregnancy
• 135,000 cases annually
• Increased risk of developing diabetes post partum
• Tight glycemic control required to prevent
  macrosomia, fetal cardiac and CNS abnormalities

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CLINICAL FEATURES

• Polyuria
• Polydipsia
• Polyphagia
• Weight loss

TYPE 1 DM-- acute, severe TYPE 2 DM-- chronic,
less severe
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???
???
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Complications of diabetes mellitus

• Acute complications
• Diabetic ketoacidosis
• Hyperosmotic nonketotic coma
• Chronic complications
• Cardiovascular diseases
• Renal damage
• Retinal damage
• Nerve degeneration
• Myopathy
• Infection

Rhinocerebral Mucormycosis
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Therapy of Diabetes Mellitus

• Diet
• Exercise
• Insulin and its enhancers
• Oral hypoglycemic drugs

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Insulin and its enhancers
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Structure of insulin
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Insulin and its enhancers

• Insulin
• 1. Pharmacological effects
• Carbohydrate metabolism reducing blood glucose
  levels by glycogenolysis ?, glycogen synthesis ?,
  gluconeogenesis ? (ketone badies ?)
• (2) Lipid metabolism fat synthesis ?, lipolysis
  ?, plasma free fatty acids ?
• (3) Protein metabolism active transport of amino
  acids ?, incorporation of amino acids into
  protein ?, protein catabolism ?
• HR ?, myocardial contractility, renal blood flow
  ?
• Mechanism of insulin actions
• Interacting with insulin receptor

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Insulin promotes glucose utilization
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Insulin and its enhancers

• Insulin
• 1. Pharmacological effects
• Carbohydrate metabolism reducing blood glucose
  levels by glycogenolysis ?, glycogen synthesis ?,
  gluconeogenesis ? (ketone badies ?)
• (2) Lipid metabolism fat synthesis ?, lipolysis
  ?, plasma free fatty acids ?
• (3) Protein metabolism active transport of amino
  acids ?, incorporation of amino acids into
  protein ?, protein catabolism ?
• HR ?, myocardial contractility, renal blood flow
  ?
• Mechanism of insulin actions
• Interacting with insulin receptor

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Insulin and its enhancers

• Insulin
• 1. Pharmacological effects
• Carbohydrate metabolism reducing blood glucose
  levels by glycogenolysis ?, glycogen synthesis ?,
  gluconeogenesis ? (ketone badies ?)
• (2) Lipid metabolism fat synthesis ?, lipolysis
  ?, plasma free fatty acids ?
• (3) Protein metabolism active transport of amino
  acids ?, incorporation of amino acids into
  protein ?, protein catabolism ?
• HR ?, myocardial contractility, renal blood flow
  ?
• Mechanism of insulin actions
• Interacting with insulin receptor

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Interaction between insulin and its receptor IRS
insulin receptor substrate tyr tyrosine P
phosphate
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Insulin promotes the translocation of glucose
transporters into the membrane
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Insulin and its enhancers

• 2. Clinical uses
• Insulin-dependent patients with diabetes mellitus
  (type 1 diabetes mellitus)
• (2) Insulin-independent patients failure to
  other drugs
• (3) Diabetic complications diabetic ketoacidosis
  (?????), hyperosmotic nonketotic coma(?????????)
• (4) Critical situations of diabetic patients
  fever, severe infection, pregnancy, trauma,
  operation
• (5) Others promotion of K uptake into the
  cells, pshychiatric disorders

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3. Preparations
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Hirsch IB NEJM 352174, 2005
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Rapid Acting Insulin Analogues

• Current agents include lispro, aspart, and
  glulisine.
• Remain monomeric after injection, resulting in
  rapid absorption, and relatively rapid onset and
  offset.
• Onset of action is 5-15 minutes, with peak action
  at 60-90 minutes and duration of 3-5 hours.
• Advantages include
• increased convenience- can take just prior to
  meal.
• better postprandial glycemic control.
• Disadvantages include
• short duration of action- can be problematic in
  Type 1 diabetic without basal insulinization, as
  with bedtime NPH.
• more expensive than regular insulin (double the
  cost).

Holleman and Hoekstra, NEJM, 337176-83,
1997 Hirsch, NEJM, 352174-83, 2005
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Actions of different insulin preparations
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Insulin and its enhancers
4. Adverse effects (1) Hypersensitivity treated
with H1 receptor antagonist, glucocorticoids
(2) Hypoglycemia adrenaline secretion
(sweating, hunger, weakenss, tachycardia, blurred
vision, headache, etc.), treated with 50
glucose (3) Lipoatrophy localized in injection
sites (4) Insulin resistance Acute stress
induced, need large dose of insulin Chronic need
gt200U/d and no complication
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Insulin and its enhancers
Insulin action enhancers Thiazolidinediones
(TDs) ???????? Rosiglitazone ????
Pioglitazone ???? Troglitazone ????
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Insulin and its enhancers
Rosiglitazone ????
Pioglitazone ????
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Insulin and its enhancers
Insulin action enhancers 1. Pharmacological
effects Selective agonists for nuclear
peroxisome proliferator-activated receptor-?
(PPAR?, ?????????????). (1) Lowering insulin
resistance (2) Lipid metabolism regulation TG,
free fatty acid ? (3) Antihypertensive
effects (4) Effect on vascular complications in
type 2 patients
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Insulin and its enhancers
2. Clinical uses Used for treatment of
insulin-resistant diabetic patients or type 2
patients 3. Adverse effects Edema, headache,
myalgia, GI reactions, hepatic damage
(troglitazone)
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Oral hypoglycemic drugs
Sulfonylureas(????) Biguanides(???) ?-Glucosidase
inhibitors(?????????) Others
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Oral hypoglycemic drugs
Sulfonylureas(????) Tolbutamide (D860)
???? Chlorpropamide ???? Glibenclamide ????
(???) Glipizide ???? Gliclazide ???? (???)
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Sulfonylureas

• 1. Pharmacological effects
• Hypoglycemic effect
• blocking ATP-sensitive K channel Ca2
  inflow ?, insulin release ?, stimulating insulin
  secretion
• increasing insulin sensitivity (long-term
  use)
• inhibit glucagon release
• (2) Antidiuretic effect
• (3) Effect on coagulation function

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Action of sulfonylureas
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Sulfonylureas

• 1. Pharmacological effects
• Hypoglycemic effect
• blocking K channel Ca2 inflow ?, insulin
  release ?, stimulating insulin secretion
• increasing insulin sensitivity (long-term
  use)
• inhibit glucagon release
• (2) Antidiuretic effect
• (3) Effect on coagulation function (Gliclazide)

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Sulfonylureas
2. Clinical uses (1) Insulin-indenpedent
diabetic patients (type 2) alone or combined
with insulin (2) Diabetes insipidus (???)
Chlorpropamide (????) antiuretic hormone (ADH)
?
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Sulfonylureas
3. Adverse effects (1) GI reactions (2) CNS
reactions (3) Hypoglycemia especially in
elderly, hepatic or renal insufficiencies (4)
Others cholestatic jaundice, hepatic damage
(Chlorpropamide), leukopenia.
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Sulfonylureas
4. Drug interactions (1) Potentiation of
hypoglycemic effects replacement in plasma
protein binding salicylic acid, sulfates,
indomethacin, penicillin, warfarin, etc.
inhibition of hepatic microsomal enzymes
chloramphenicol, warfarin (2) Attenuation of
hypoglycemic effects induction of hepatic
microsomal enzymes phenytoin, phenobarbital,
etc. interactions in pharmacodynamics
glucagon, thiazides, etc.
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Oral hypoglycemic drugs
Biguanides(???) Metformin
????(???) Phenformin ????(????)
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Biguanides
1. Pharmacilogical effects increasing glucose
uptake in fat tissues and anaerobic glycolysis in
skeletal muscles decreasing glucose
absorption in gut and glucagon release  2.
Clinical uses mild insulin-independent
patients with obesity   3. Adverse effects
severe lactic acidosis (less for metformin),
malabsorption of vitamin B12 and folic acid 
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Oral hypoglycemic drugs
?-Glucosidase inhibitors(?????????)
Acarbose ???? Reducing intestinal
absorption of starch (??), dextrin (??), and
disaccharides (??) by inhibiting the action of
intestinal brush border ?-glucosidase
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Oral hypoglycemic drugs
Others Repaglinide ???? Oral insulin
secretagogue
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Repaglinide (???????)

• Pharmacological effects
• Repaglinide lowers blood glucose by stimulating
  the release of insulin from the pancreas.
• It achieves this by closing ATP-dependent
  potassium channels in the membrane of the beta
  cells. This depolarizes the beta cells, opening
  the cells' calcium channels, and the resulting
  calcium influx induces insulin secretion
• Clinical uses
• Type2 DM, diabetic nephropathy, elder DM patient

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Incretin Mimetics

• Mechanism of Action
• Act as an incretin? enhance insulin secretion in
  response to an oral glucose load.
• Suppress post-prandial glucagon secretion in a
  glucose-dependent manner
• Delay gastric emptying
• Centrally suppress appetite
• Preserve beta cell mass by reducing apoptosis and
  increased neogenesis (animal models).

• Keating, Drugs. 65(12)1681-92, 2005.
• Riddle and Drucker. Diabetes Care 2006
  29435-49.

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Incretin Mimetics

• Exenatide (Byetta) is first
• incretin mimetic on market.
• Synthetic version of salivary protein found in
  the Gila monster?53 overlap with human GLP-1.
• Must be taken as a BID injection w/in 60 mins
  prior to meal
• Major side effects nausea, vomiting, diarrhea.
  Increases the risk of Acute pancreatitis.
• Use not recommended in severe renal impairment.
• Not recommended as monotherapy
• To be used as add on therapy with SU, metformin,
  or TZDs
• Increases the risk of Hypoglycemia when added to
  SU treatment.
• Major advantage is weight loss (5 kg) as well as
  maintained effect (?preserved beta cell
  function).
• Efficacy decreases A1C 1.0.

Keating, Drugs 2005 65(12)1681-92
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Dipeptidylpeptidase IV (DPP-IV) Inhibitors

• Mechanism of Action
• Acts to prevent breakdown of intrinsic GLP-1,
  thereby increasing portal GLP-1 levels
• Acts as an incretin? enhances insulin secretion
  in response to an oral glucose load.
• Suppresses post-prandial glucagon secretion in a
  glucose-dependent manner
• Preserves beta cell mass by reducing apoptosis
  and increased neogenesis (animal models).
• Sitagliptin (Januvia) is first DPP-IV inhibitor
  on market.
• Effective as monotherapy or when used in
  conjunction with metformin or a
  thiazolidinedione.
• Appears to maintain efficacy (?preserved beta
  cell fxn).
• Efficacy decreases A1C 0.8.

• Riddle and Drucker. Diabetes Care 2006
  29435-49.

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Case 1

• 50y/o, Chinese Male,
• CC Hyperglycemia found 2 m
• PE BMI 29 Kg/m2 WC 102cm
• Lab Findings FBG 155mg/dl, 2hPG 276mg/dl,
  HbA1c 7.5
• Which DRUG or DRUGS will we order?

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Treatment Strategies Beyond Lifestyle

• In general, try to initiate pharmacotherapy with
  an oral agent in newly diagnosed type 2 diabetics
  unless
• Fasting plasma glucose is gt300 mg/dl with
  ketonemia or ketonuria
• Markedly symptomatic
• In patients who need insulin initially, often can
  be switched to oral agents after 6-8 weeks when
  glucose toxicity resolves

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Answer to Case 1 ( A newly diagnosed type 2 DM
patient with obesity)

• Lifestyle intervention
• Metformin 500mg q.d.-t.i.d

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Failure of a Single Oral Agent

• Type 2 diabetes is a progressive disease, with
  ?d loss of beta cell function over time.
• Need to progress to multi-drug therapy or add
  insulin in order to maintain a similar level of
  glycemic control.
• If glycemic goals are not met with agent in one
  class, we must add second agent with different
  mechanism of action or add insulin

1Kahn et al. N Engl J Med, 3552427, 2006

• ADA consensus algorithm recommends addition of
  a SU, thiazolidinedione, or insulin if metformin
  therapy is not effective in getting patients to
  goal A1C.2

2Nathan et al. Diabetes Care. 291963-1972,
2006.
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Algorithm for the management of T2DM
From China Guideline for Type 2 Diabetes
(CDS,2007)
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Algorithm for the management of T2DM (Cont)
From China Guideline for Type 2 Diabetes
(CDS,2007)
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Use of Oral Agents to Optimize Glycemic Control
Conclusions

• Choice of oral agents needs to be matched with
  patient characteristics (thin vs. obese) as well
  as concurrent medical issues (renal, hepatic,
  cardiopulmonary status).
• Diabetes is a progressive disease, and will
  require an increasing number of agents and/ or
  addition of insulin as the duration of diabetes
  increases.
• Each oral agent can only improve A1C a maximum of
  2, so if poor control persists on multiple
  agents, insulin is needed.

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Use Of Insulin In Type 2 Diabetes

• Indications
• When glycemic control deteriorates despite
  combination oral agents.
• Surgery in patients with type 2 DM (transient)
• Pregnancy
• Method
• Start with bedtime intermediate (NPH) or long
  acting (glargine, detemir) insulin in addition to
  oral agents.
• If doesnt work, switch to basal-bolus therapy as
  used in conventional type 1 DM treatment
• Can continue metformin.
• Stop insulin secretagogues.

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Basal/Bolus Insulin Absorption Pattern
w/ Standard Insulin Preparations
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Breakfast
Lunch
Dinner
50
Plasma Insulin µU/ml)
25
NPH
400
1600
2000
2400
400
800
1200
800
Time
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Basal-Bolus Treatment withRapid and Long Acting
Analogues
Breakfast
Lunch
Dinner
Glulisine Glulisine Glulisine
Plasma Insulin
Glargine
400
1600
2000
2400
400
800
1200
800
Time
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Insulin Pump and Glucose Monitoring
Insulin Pump Open Loop Patient sets basal
infusion rate and w/ superimposed boluses
Continuous Glucose Monitor
Closed Loop insulin pump system is ultimate
goal infusion rate adjusted based on input from
continuous glucose monitor.
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Case 2

• 64y/o, Chinese Male.
• CCpolydipsia,polyuria,polyphagia 12y
• lower limb edema 3 m
• Metformin 500mg bid Glipizide 80mg tid
• PE BMI 22kg/m2, WC 78cm, decreased sensation
  and medium pitting edema in both lower limbs
• Lab Findings
• UA PRO 3,GLU 2
• FBG 188mg/dl, 2hPG 266 mg/dl
• HbA1c 8.3

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Case2 (Cont)

• Liver function tests nl transaminase, Alb 28g/l
• SCr1.5mg/dl, CCr 52ml/min
• Which DRUG or DRUGS should we Prescribe?

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Answer to case 2 (long diabetes history with
diabetic Nephropathy and Chronic renal
insufficiency )

• Should start with insulin treatment
• Regimen
• 1. Regular insulin or rapid acting insulin
  analogs tid pre-meal NPH or long acting
  insulin analog at bedtime
• 2. Insulin Pump