Download Insulin and oral hypoglycemic drugs

Insulin and oral
hypoglycemic drugs
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
Glucose metabolism
and the regulation by
insulin and glucogan
Diabetes mellitus:
Insulin  or its
responses 
 blood glucose 
 Acute or chronic
symptoms
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
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 (酮症酸中毒）
CLASSIFICATION
 TYPE 2



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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 (高血糖高渗
性非酮症综合征), nephropathy, retinopathy,
neuropathies
Disease can be delayed or prevented with life
style changes
Natural History of Type 2 Diabetes
Obesity
Glucose
(mg/dL)
Relative
Function
(%)
IGT
Diabetes
350
300
250
200
150
100
50
250
200
150
100
50
0
Uncontrolled hyperglycemia
Post-meal
Glucose
Fasting
Glucose
Insulin Resistance
Insulin Level
“Beta-cell failure”
-10
*IGT = impaired glucose tolerance
-5
0
5
10
15
20
25
30
Years of Diabetes
Adapted from International Diabetes Center (IDC)
Minneapolis, Minnesota
CLASSIFICATION
 SECONDARY CAUSES





Exocrine pancreas disease: pancreatitis
Genetic syndromes: Downs, Turners
Infections: CMV, Congenital rubella
Drugs: Glucocorticoids, Dilantin, beta
agonists
Endocrinopathies: Cushing's, Acromegaly
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
CLINICAL FEATURES

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

Polyuria
Polydipsia
Polyphagia
Weight loss
TYPE 1 DM-- acute, severe
TYPE 2 DM-- chronic, less severe
正常人
糖尿病
尿崩症
Complications of diabetes mellitus
 Acute complications


Diabetic ketoacidosis
Hyperosmotic nonketotic coma
 Chronic complications

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
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
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Cardiovascular diseases
Renal damage
Retinal damage
Nerve degeneration
Myopathy
Infection
Rhinocerebral
Mucormycosis
Therapy of Diabetes Mellitus
 Diet
 Exercise
 Insulin and its enhancers
 Oral hypoglycemic drugs
Insulin and its enhancers
Structure of insulin
Insulin and its enhancers
Insulin
1. Pharmacological effects
(1) 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 
(4) HR , myocardial contractility, renal blood flow 
Mechanism of insulin actions
Interacting with insulin receptor
Insulin promotes glucose utilization
Insulin and its enhancers
Insulin
1. Pharmacological effects
(1) 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 
(4) HR , myocardial contractility, renal blood flow 
Mechanism of insulin actions
Interacting with insulin receptor
Insulin and its enhancers
Insulin
1. Pharmacological effects
(1) 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 
(4) HR , myocardial contractility, renal blood flow 
Mechanism of insulin actions
Interacting with insulin receptor
Interaction
between insulin
and its receptor
IRS: insulin receptor
substrate
tyr: tyrosine
P: phosphate
Insulin promotes the
translocation of glucose
transporters into the
membrane
Insulin and its enhancers
2. Clinical uses
(1) Insulin-dependent patients with diabetes
mellitus (type 1 diabetes mellitus)
(2) Insulin-independent patients: failure to other drugs
(3) Diabetic complications: diabetic ketoacidosis (酮症
酸中毒), hyperosmotic nonketotic coma（高渗性非酮症性昏
迷）
(4) Critical situations of diabetic patients: fever,
severe infection, pregnancy, trauma, operation
(5) Others: promotion of K+ uptake into the cells,
pshychiatric disorders
3. Preparations
Properties
Preparations
Onset
Peak
Duration
Fast-acting
Regular insulin
0.5-1
h
2-3 h
6-8 h
Intermmediateacting
Neutral protamine
hagedorn
2-4 h
6-10 h
12-18 h
Long-acting
Protamine zinc insulin
suspension
3-6 h
6-10 h
24-36 h
Hirsch IB NEJM 352:174, 2005
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:
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increased convenience- can take just prior to meal.
better postprandial glycemic control.
 Disadvantages include:
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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, 337:176-83, 1997
Hirsch, NEJM, 352:174-83, 2005
Actions of different insulin preparations
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 >200U/d and no complication
Insulin and its enhancers
Insulin action enhancers
Thiazolidinediones (TDs)
Rosiglitazone 罗格列酮
Pioglitazone 吡格列酮
Troglitazone 曲格列酮
噻唑烷酮类化合物
Insulin and its enhancers
Rosiglitazone
罗格列酮
Pioglitazone
吡格列酮
Insulin and its enhancers
Insulin action enhancers
1. Pharmacological effects
Selective agonists for nuclear peroxisome
proliferator-activated receptor- (PPAR, 过氧化物酶增殖体激活受
体).
(1) Lowering insulin resistance
(2) Lipid metabolism regulation: TG, free fatty acid 
(3) Antihypertensive effects
(4) Effect on vascular complications in type 2 patients
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)
Oral hypoglycemic
drugs
Sulfonylureas（磺酰脲类）
Biguanides（双胍类）
-Glucosidase inhibitors（葡萄糖苷酶抑制药）
Others
Oral hypoglycemic drugs
Sulfonylureas（磺酰脲类）
Tolbutamide (D860) 甲磺丁脲
Chlorpropamide 氯磺丙脲
Glibenclamide 格列本脲 (优降糖)
Glipizide 格列吡嗪
Gliclazide 格列齐特 (达美康)
Sulfonylureas
1. Pharmacological effects
(1)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
Action of sulfonylureas
Sulfonylureas
1. Pharmacological effects
(1)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)
Sulfonylureas
2. Clinical uses
(1) Insulin-indenpedent diabetic patients (type 2):
alone or combined with insulin
(2) Diabetes insipidus (尿崩症):
Chlorpropamide (氯磺丙脲): antiuretic hormone (ADH) 
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.
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.
Oral hypoglycemic drugs
Biguanides（双胍类）
Metformin 二甲双胍（甲福明）
Phenformin 苯乙双胍（苯乙福明）
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
Oral hypoglycemic drugs
-Glucosidase inhibitors（葡萄糖苷酶抑制药）
Acarbose 阿卡波糖
Reducing intestinal absorption of starch (淀粉),
dextrin (糊精), and disaccharides (二糖) by
inhibiting the action of intestinal brush border
-glucosidase
Oral hypoglycemic drugs
Others
Repaglinide
瑞格列奈
Oral insulin secretagogue
Repaglinide (餐时血糖调节剂)
 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
Incretin Mimetics
 Mechanism of Action:
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Act as an incretin enhance insulin secretion in response
to an oral glucose load.
Suppress post-prandial glucagon secretion in a glucosedependent 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; 29:435-49.
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.
Exenatide
GLP-1
Human
H AE G T F TSD V S SY
K E F I AW
A LVKGR
VK R -NH2
SYLLEGQ
GQAAAKE
Site of DPP-IV Inactivation
 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
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To be used as add on therapy with SU, metformin, or TZD’s
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
Dipeptidylpeptidase IV (DPP-IV) Inhibitors
 Mechanism of Action:
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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; 29:435-49.
Case 1
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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?
Treatment Strategies Beyond Lifestyle
 In general, try to initiate pharmacotherapy with an
oral agent in newly diagnosed type 2 diabetics unless:
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Fasting plasma glucose is >300 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
Answer to Case 1 ( A newly diagnosed type
2 DM patient with obesity)
 Lifestyle intervention
 Metformin 500mg q.d.-t.i.d
“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, 355:2427, 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. 29:1963-1972, 2006.
Algorithm for the management of T2DM
Overweight or
obese patients
(BMI >=24Kg/m2)
Diet,exercise,
weight loss
+
Metformin
3 month later HbA1c﹥6.5%
Add one or several agents below: Sulfonylurea
or Meglitinide (one of the two), Glitazones ,
Alpha-Glucosidase Inhibitor
3 month later HbA1c > 6.5%
Add insulin
From: China Guideline for Type 2 Diabetes (CDS,2007)
Algorithm for the management of T2DM (Cont’)
Non-obese Patients
(BMI﹤24kg/m2)
Diet, exercise, weight loss +
One or several agents below: Metformin,
Sulfonylurea or Meglitinide (one of the two),
Thiazolidinedione, Alpha-Glucosidase Inhibitor
3 month later HbA1c > 6.5%
Add insulin
From: China Guideline for Type 2 Diabetes (CDS,2007)
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.
Use Of Insulin In Type 2 Diabetes
 Indications
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When glycemic control deteriorates despite
combination oral agents.
Surgery in patients with type 2 DM (transient)
Pregnancy
 Method:
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Start with bedtime intermediate (NPH) or long
acting (glargine, detemir) insulin in addition to oral
agents.
If doesn’t work, switch to basal-bolus therapy as
used in conventional type 1 DM treatment
• Can continue metformin.
• Stop insulin secretagogues.
Basal/Bolus Insulin Absorption Pattern w/
Standard Insulin Preparations
Plasma Insulin µU/ml)
75
Breakfast
Lunch
Dinner
50
REG
REG
REG
25
4:00
NPH
8:00
12:00
16:00
Time
20:00
24:00
4:00
8:00
Plasma Insulin
Basal-Bolus Treatment with
Rapid and Long Acting Analogues
Breakfast
Aspart
Lunch
Aspart
Dinner
Aspart
or
Lispro
or
or
Lispro
or
or
Lispro
or
Glulisine
Glulisine
Glulisine
Glargine
4:00
8:00
12:00
16:00
Time
20:00
24:00
4:00
8:00
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.
Case 2
 64y/o, Chinese Male.
 CC:polydipsia,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%;
Case2 (Cont’)
 Liver function tests: nl transaminase,
Alb 28g/l
SCr:1.5mg/dl, CCr: 52ml/min
 Which DRUG or DRUGS should we
Prescribe?
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 premeal + NPH or long acting insulin analog at bedtime
2. Insulin Pump