Pancreatic hormones & antidiabetic drugs Huifang Tang Department of pharmacology Email:...

Pancreatic hormones Pancreatic hormones & antidiabetic drugs& antidiabetic drugs

Huifang Tang

Department of pharmacologyEmail: [email protected]

mailto:[email protected]

History of Diabetes1869

Paul Langerhans discovers islet cells in the pancreas.

1889 Mehring and Minkowski produce DM in dogs by removing the pancreas.

1921Banting and Best find a pancreatic extract that lowers blood glucose in pancreatectomized dogs.

VOL 101 / NO 4 / APRIL 1997 / POSTGRADUATE MEDICINE

Dr. F.G. Banting, Mr. C.H. Best, Mr. J.B. Collip and Prof. J.J.R. MacLeod discovered insulin in 1921 at the University of Toronto.

Overview of Glucose RegulationOverview of Glucose Regulation

-cell insulin -cell insulin secretionsecretion

Glucose

Amended from Dinneen SF. Diabetes Med. 1997;14(suppl 3):S19-24.

Defective insulin secretion

Insulin actionResistance to insulin action

Persistent Hepatic Glucose Output

SulfonylureasMeglitinidesSulfonylureasMeglitinides

Incretin analogsDPP-IV InhibitorsIncretin analogsDPP-IV Inhibitors

MetforminMetformin

ThiazolidinedionesThiazolidinediones

Amylin analogsAmylin analogs

Alpha glucosidase inhibitorsAlpha glucosidase inhibitors

Different forms of diabetes Different forms of diabetes mellitusmellitus

Complications of diabetes mellitusComplications of diabetes mellitus

Acute complicationsAcute complications Diabetic ketoacidosis Diabetic ketoacidosis (( 酮症酸中毒酮症酸中毒 ))

Hyperosmotic nonketotic comaHyperosmotic nonketotic coma(( 高渗性非酮症性昏迷）高渗性非酮症性昏迷） Chronic complicationsChronic complications Cardiovascular diseasesCardiovascular diseases Renal damageRenal damage Retinal damageRetinal damage Nerve degenerationNerve degeneration Infection Infection Myopathy Myopathy etc.etc.

Pharmacological therapy Insulin. Oral hypoglycemic drugs Insulin sensitizers

Insulin secretagogues

α-glucosidase inhibitors

A.A. Insulin Insulin

A.A. InsulinInsulin

InsulinInsulin

1. 1. Pharmacological effectsPharmacological effects(1) Carbohydrate metabolism:(1) Carbohydrate metabolism: reducing reducing blood glucose levels by gycogenolysis blood glucose levels by gycogenolysis , , glycogen synthesis glycogen synthesis , gluconeogenesis , gluconeogenesis (ketone badies (ketone badies ))(2) lipid metabolism:(2) lipid metabolism: fat synthesis fat synthesis , , lipolysis lipolysis , plasma free fatty acids , plasma free fatty acids (3) Protein metabolism:(3) Protein metabolism: active transport of active transport of amino acids amino acids , incorporation of amino acids into , incorporation of amino acids into protein protein , protein catabolism , protein catabolism (4) Mechanism of insulin actions(4) Mechanism of insulin actions Interacting with insulin receptorInteracting with insulin receptor

Interaction betInteraction between insulin aween insulin and its receptornd its receptorIRS:IRS: insulin receptor insulin receptorsubstrate substrate tyr:tyr: tyrosine tyrosine P:P: phosphate phosphate

Insulin promotes the Insulin promotes the translocation of gluctranslocation of glucose transporters into ose transporters into the membranethe membrane

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

A.A. InsulinInsulin

3. Preparations

A.A. InsulinInsulin

Approximate Pharmacokinetic Profiles of Human Insulins and Insulin Analogues

Hirsch. NEJM. 2005; 352:174-83.

4.4. Adverse effects Adverse effects

(1) Hypersensitivity: (1) Hypersensitivity: treated with Htreated with H11 receptor antagonist, glucocorticoids receptor antagonist, glucocorticoids

(2) Hypoglycemia:(2) Hypoglycemia: adrenaline secretion adrenaline secretion (sweeting, hunger, weakenss, tachycardia, (sweeting, hunger, weakenss, tachycardia, blurred vision, headache, blurred vision, headache, etc.etc.), treated with ), treated with 50% glucose50% glucose

(3) Insulin resistance: (3) Insulin resistance: Acute: stress induced, need large dose of Acute: stress induced, need large dose of insulininsulinChronic: need >200U/d and no complicationChronic: need >200U/d and no complication

(4) Lipoatrophy(4) Lipoatrophy: : localized in injection sitelocalized in injection sitess

A.A. InsulinInsulin

History In 1942, Janbon and colleagues noted that some sulfonamides ( 磺胺类 )caused hypoglycemia in experiment animal.---Carbutamide （氨磺丁脲） became the first clinically useful sulfonylurea （磺酰脲类） for treatment of diabets.

In the early 1950s, Clinical trials of tolbutamide（甲苯磺丁脲） , the first widely used member of this group, were instituted in type 2 DM patients.

During the 1920s, biguanides were investigated for use in diabets, but they are overshadowed by the discovery of insulin.

In 1997, the first member of a new class of oral insulin secretagogues called meglitinide(美格替奈 ) was approved for clinical use.

In 1997, Thiazolidinediones were introduced as the second major class of insulin sensitizers.In 2000, the first of these agents, troglitazone was withdrawn from use in the United Stats.

B. Oral hypoglycemic drugs

B. Oral hypoglycemic

drugs Insulin secretagogues( 促胰岛素分泌剂 ):

SulfonylureasSulfonylureas(( 磺酰脲类磺酰脲类 ))RepaglinideRepaglinide (( 瑞格列奈瑞格列奈 ))GLP-1 receptor agonistGLP-1 receptor agonistDPP-4 inhibitorDPP-4 inhibitor

Insulin sensitizers （胰岛素增敏剂） :Thiazolidinediones (TDs)Thiazolidinediones (TDs)BiguanidesBiguanides

α-glucosidase inhibitors

1. 1. SulfonylureasSulfonylureas

Tolbutamide Tolbutamide (D860) (D860) 甲苯磺丁脲甲苯磺丁脲Chlorpropamide Chlorpropamide 氯磺丙脲氯磺丙脲GlibenclamideGlibenclamide 格列本脲格列本脲 (( 优降糖优降糖 ) ) Glipizide Glipizide 格列吡嗪格列吡嗪Gliclazide Gliclazide 格列齐特格列齐特 (( 达美康达美康 ))

B. Oral hypoglycemic drugs -1

格列本脲 ( 优降糖 )

格列吡嗪

格列齐特 ( 达美康 )

氯磺丙脲甲苯磺丁脲

格列美脲

Mechanisms of Mechanisms of Action of sulfonylureasAction of sulfonylureas

SulfonylureasSulfonylureas1.1. Pharmacological effects Pharmacological effectsAct by binding to specific receptors (SUR1) on the beta cells and promoting insulin secretion. Blocking K+ channel: Blocking K+ channel: Ca2+ inflow Ca2+ inflow , insulin , insulin release release ,,Stimulating insulin secretionStimulating insulin secretionIncreasing insulin sensitivity (long-term use)Increasing insulin sensitivity (long-term use)1st generation agents (tolbutamide, tolazemide, chlorpropamide) rarely used today2nd generation agents (glyburide, glipizide and glimeperide) are more potent and all ~equally effective in maximal dose.


Sulfonylureas – Caveats in UseSulfonylureas – Caveats in Use GlyburideGlyburide((格列本脲格列本脲 )) Longer duration of action, active hepatic Longer duration of action, active hepatic

metabolites, renally excreted metabolites, renally excreted May want to avoid in adults >65 years oldMay want to avoid in adults >65 years old GlipizideGlipizide （格列吡嗪）（格列吡嗪） Shorter duration of actionShorter duration of action GlimepirideGlimepiride （格列美脲）（格列美脲） Largely excreted in bileLargely excreted in bile All are hepatically metabolized and should be All are hepatically metabolized and should be

used cautiously with advanced liver diseaseused cautiously with advanced liver disease Start with lowest dose and titrate slowlyStart with lowest dose and titrate slowly


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)


3. Adverse effects

Major side effects- weight gain- hypoglycemia, especially in the elderly or in patients with impaired renal function.Major advantages- low price (generic glip $10-20/month) - long track record of safety.Others: leukopenia, cholestatic jaundice( 胆汁淤积性黄疸 ), hepatic damage

B. Oral hypoglycemic drugs-1

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, warfaren(2) Attenuation of hypoglycemic effects induction of hepatic microsomal enzymes: phenytoin, phenobarbital, etc. interactions in pharmacodynamics: glucagon, thiazides, etc.


2.2.Meglitinides Meglitinides (Non-SU Insulin Secretagogues)(Non-SU Insulin Secretagogues)

Prandial glucose regulators (Prandial glucose regulators ( 餐时血糖调节餐时血糖调节剂剂 ))

Act by binding to SUR1 on beta cells to promote insulin Act by binding to SUR1 on beta cells to promote insulin secretion. secretion.

Repaglinide (PrandinRepaglinide (Prandin ，瑞格列奈，瑞格列奈 )) and and Nateglinide Nateglinide (Starlix(Starlix ，那格列奈，那格列奈 )) are current agents in class. are current agents in class.

Major side effect Major side effect is hypoglycemia. is hypoglycemia. Major advantage Major advantage is rapid onset and offsetis rapid onset and offset Can dose just prior to meals with better post-prandial controlCan dose just prior to meals with better post-prandial control Fewer overnight lowsFewer overnight lows Ability to skip the dose if skip the meal. Ability to skip the dose if skip the meal. Efficacy for repaglinide appears to be similar to SU’sEfficacy for repaglinide appears to be similar to SU’s


Mechanism of action

3. GLP-1 3. GLP-1 （（ glucogen-like peptide1)receptor agglucogen-like peptide1)receptor agonist and DPP-4 inhibitoronist and DPP-4 inhibitor


GLP-1 receptor agonist and DPP-4 inhibitorB. Oral hypoglycemic drugs-3

GLP-1 receptor agonist and DPP-4 inhibitor


GLP-1 GLP-1 （（ glucogen-like peptide1)receptor agonistglucogen-like peptide1)receptor agonist

依克那肽

利拉鲁肽

GLP-1 GLP-1 （（ glucogen-like peptide1)receptor agonistglucogen-like peptide1)receptor agonist

Exenatide(Exenatide( 依克那肽依克那肽 )) Exenatide is a synthetic version of Exenatide is a synthetic version of exendin-4exendin-4, a , a

hormone found in the saliva of the Gila hormone found in the saliva of the Gila monster that was first isolated by Dr. John Eng monster that was first isolated by Dr. John Eng in 1992in 1992..

a 39-amino-acid peptide, an insulin secretagogue, a 39-amino-acid peptide, an insulin secretagogue, with glucoregulatory effectswith glucoregulatory effects

Mechanism of actionMechanism of action:: It displays biological It displays biological properties similar to human glucagon-like properties similar to human glucagon-like peptide-1 (GLP-1), a regulator of glucose peptide-1 (GLP-1), a regulator of glucose metabolism and insulin secretionmetabolism and insulin secretion


Exenatide(Exenatide( 依克那肽依克那肽 )) Must be taken as a BID injection w/in 60 mins prior to mMust be taken as a BID injection w/in 60 mins prior to m

ealeal Major side effects:Major side effects: nausea, vomiting, diarrhea. Increase nausea, vomiting, diarrhea. Increase

s the risk of Acute pancreatitis. s the risk of Acute pancreatitis. NNot recommended in severe renal impairment. ot recommended in severe renal impairment. Not recommended as monotherapyNot recommended as monotherapy To be used as add on therapy with SU, metformin, or TZTo be used as add on therapy with SU, metformin, or TZ

D’sD’s Increases the risk of Hypoglycemia when added to SU tIncreases the risk of Hypoglycemia when added to SU t

reatment.reatment. Major advantage Major advantage : : weight lossweight loss (~5 kg) as well as maintai (~5 kg) as well as maintai

ned effect (preserved beta cell function).ned effect (preserved beta cell function). Efficacy: decreases A1C ~1.0%.Efficacy: decreases A1C ~1.0%.


DPP-4 (dipeptidyl peptidase 4 enzyme) inhibitorDPP-4 (dipeptidyl peptidase 4 enzyme) inhibitor

Sitagliptin phosphate(Sitagliptin phosphate( 磷酸西列他汀）磷酸西列他汀） Mechanism of actionMechanism of action:: Acts to prevent breakdown of intrinsic GLP-1, thereby Acts to prevent breakdown of intrinsic GLP-1, thereby

increasing portal GLP-1 levelsincreasing portal GLP-1 levels Acts as an incretin enhances insulin secretion in Acts as an incretin enhances insulin secretion in

response to an oral glucose load.response to an oral glucose load. Suppresses post-prandial glucagon secretion in a Suppresses post-prandial glucagon secretion in a

glucose-dependent mannerglucose-dependent manner Preserves beta cell mass by reducing apoptosis and Preserves beta cell mass by reducing apoptosis and

increased neogenesis (animal models).increased neogenesis (animal models).


Sitagliptin phosphate(Sitagliptin phosphate( 磷酸西列他汀）磷酸西列他汀） Sitagliptin (Januvia) is first DPP-IV inhibitor on

market. Effective as monotherapy or when used in conj

unction with metformin or a thiazolidinedione. Appears to maintain efficacy (preserved beta ce

ll fxn). Efficacy: decreases A1C ~0.8%.


Insulin sensitizersInsulin sensitizersBiguanidesBiguanides

MetforminMetformin 二甲双胍二甲双胍 PhenforminPhenformin 苯乙双胍苯乙双胍1. Pharmacological 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, malabsorption of vitamin B12 and folic acid


Mechanism of action

BiguanidesBiguanides Mechanism of actionMechanism of action not well understood, but not well understood, but

causes inhibition of hepatic glucose production. causes inhibition of hepatic glucose production. Metformin is only agent in this class available Metformin is only agent in this class available

in US.in US. Major side effectMajor side effect GI intolerance (20-30%): bloating, anorexia, diarrhea, GI intolerance (20-30%): bloating, anorexia, diarrhea,

and flatulence. Lactic acidosis is rare, but may be and flatulence. Lactic acidosis is rare, but may be severe.severe.

Major advantages: Major advantages: Lack of weight gainLack of weight gain Absence of hypoglycemiaAbsence of hypoglycemia Low cost with generic prep.Low cost with generic prep.


Thiazolidinediones (TZDs) Thiazolidinediones (TZDs) 噻唑烷噻唑烷酮类化合物酮类化合物

RosiglitazoneRosiglitazone 罗格列酮罗格列酮 Pioglitazone Pioglitazone 吡格列酮吡格列酮 TroglitazoneTroglitazone 曲格列酮曲格列酮


RosiglitazoRosiglitazone ne 罗格列酮罗格列酮

PioglitazoPioglitazone ne 吡格列酮吡格列酮


Insulin action enhancersInsulin action enhancers1.1. Pharmacological effects Pharmacological effects

Selective agonists for nuclear peroxisome Selective agonists for nuclear peroxisome proliferator-activated receptor-proliferator-activated receptor- (PPAR (PPAR , , 过氧化过氧化物酶增殖体激活受体物酶增殖体激活受体 ), by enhancing peripheral ), by enhancing peripheral insulin sensitivity, esp. at muscle and adipose insulin sensitivity, esp. at muscle and adipose tissue, via activation of PPARγtissue, via activation of PPARγ, , increasing increasing glucose transport into muscle and adipose glucose transport into muscle and adipose tissue.tissue.

(1) Lowering insulin resistance

(2) Lipid metabolism regulation: TG, free fatty acid

(3) Antihypertensive effects

B. Oral hypoglycemic drugs -2-2

Mechanism of action

2. Clinical uses2. Clinical uses

used for treatment of insulin-resistant diabetic patients or type 2 patients

3. Adverse effects3. Adverse effects

Edema, headache, myalgia, GI reactions, hepatic damage (troglitazone)


B.B. Oral hypoglycemic drugsOral hypoglycemic drugs -3-3

Alpha-Glucosidase inhibitorsAlpha-Glucosidase inhibitors Acarbose-Precose Acarbose-Precose 阿卡波糖阿卡波糖 19919966 Miglitol-Glyset Miglitol-Glyset 米格列醇米格列醇 19199898 Voglibose Voglibose 伏格列波糖伏格列波糖

Reducing intestinal absorption of starch ( 淀粉 ), dextrin ( 糊精 ), and disaccharides ( 二糖 ) by inhibiting the action of alpha-glucosidase enzymes in the brush border of the small intestines.

AcarbosAcarbose e 阿卡波糖阿卡波糖B.B. Oral hypoglycemic drugsOral hypoglycemic drugs -3-3

Mechanism of Mechanism of AcarbosAcarbose e B.B. Oral hypoglycemic drugsOral hypoglycemic drugs-3-3

Alpha-Glucosidase Inhibitors Alpha-Glucosidase Inhibitors – Caveats in Use– Caveats in Use

Acarbose has minimal systemic absorption, but some hepatic metabolism occurs.

Contraindicated with advanced liver disease Miglitol has greater systemic absorption Not metabolized by the liver Renally excreted, and hence should not be used in

renal failure (creatinine >2) Voglibose in contrast to acarbose, has less of GI

side effects. It is also more economical compared to acarbose.

Major side effectMajor side effect : : GI intolerance, GI intolerance, including bloating, cramping, and including bloating, cramping, and flatulenceflatulence, diarrhea, diarrhea… need to titrate very … need to titrate very slowly. slowly.

Major advantageMajor advantage: : absence of absence of hypoglycemia when used as monotherapy. hypoglycemia when used as monotherapy.

Alpha-Glucosidase inhibitorsAlpha-Glucosidase inhibitors

B.B. Oral hypoglycemic drugsOral hypoglycemic drugs -3-3

Summary Medication Site of

Action/MechanismSide-Effects

Sulfonylurea (eg. glyburide) Augments insulin secretion, binds SUR

Hypoglycemia, caution renal insufficiency, elderly

Thiazolidinediones (eg. rosiglitazone)

PPARg receptor/increased insulin sensitivity

Liver, LE edema, congestive heart failure, MI

Biguanide (metformin) Reduced hepatic gluconeogenesis

GI upset, Lactic acidosis (very rare), only use if creatinine<1.5 mg/dl

Glinides (repaglinide) Bind SUR, short action Hypoglycemia, caution in renal insufficiency

Alpha-glucosidase inhibitors (acarbose)

Inhibits brush border enzyme/Reduce glucose absorption

Flatulence, diarrhea

Incretins/GLP-1 (exenatide) Stimulates insulin, delays gastric emptying, satiety

Nausea, vomiting (given by injection)

DPP4 Inhibitors (vildagliptin)

Inhibits GLP1 breakdown GI side effects

Pancreatic hormones & antidiabetic drugs Huifang Tang Department of pharmacology Email:...

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