Diabetes

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Almustansiriya medical college , medical college ... Al Mustansiriya. Al Mustansiriya Medical College , ...... San Diego
Incretin--Based Therapies for the Incretin Treatment of Type 2 Diabetes: Update on the Benefits and Risks Dr. Abdulameer Abdullah AlAl-Ashbal Ass.Prof. ; Consultant Diabetologist Almustansiriya medical college , Department of Medicine ; Alyermouk Teaching Hospital

Dr. Abdulameer Al Al--Ashbal Consultant Diabetologist; Ass. Professor of Medicine Al Mustansiriya Medical College , Department of Medicine ; Alyermouk Teaching Hospital

My disclosure : No financial relationships with any commercial interests

Very important note  Almost all the references mentioned by this lecture which deal with incretin hormones and benefits of subsequent incretin-based drugs are sponsored or supported by drugs manufactures  While almost all the references which deal with adverse effects and particularly serious ones are not sponsored or supported by drugs manufactures

The gastrointestinal tract has a crucial role in the control of

energy homeostasis through its role in

the digestion, absorption, and assimilation of ingested nutrients. Dr. Abdulameer Abdullah Al- Ashbal ; Ass.Prof. , Consultant Diabetologist

The role of

Insulin in

glucose homeostasis is a firmly established concept and forms the cornerstone of discussions of the pathophysiolgy of diabetes.

Dr. Abdulameer Abdullah Al- Ashbal ; Ass.Prof. , Consultant Diabetologist

However, how glucose enters the blood stream has profound effects on magnitude of stimulatory effect of

glucose on insulin secretion Dr. Abdulameer Abdullah Al- Ashbal ; Ass.Prof. , Consultant Diabetologist

The observation that in response to hyperglycemic stimuli, oral glucose elicits a greater insulin response than

intravenous glucose, is termed , which accounts for up to 60% of postprandial insulin release in healthy people

The observation that in response to hyperglycemic stimuli, oral glucose elicits a greater insulin response than

intravenous glucose, is termed

“The Incretin Effect “ , which accounts for up to 60% of postprandial insulin release in healthy people

The observation that in response to hyperglycemic stimuli, oral glucose elicits a greater insulin response than

intravenous glucose, is termed

“The Incretin Effect “ , which accounts for up to 60 60% % of postprandial insulin release in healthy people

The incretin effect Energy administration via The gut The parenteral route

Glucose (Insulin secretagogue)

Insulin release

Glucose (Insulin secretagogue)

Insulin release

The incretin effect Energy administration via The gut The parenteral route

Glucose



(Insulin secretagogue)

Glucose (Insulin secretagogue)

Gut--derived signals Gut (Potent insulin secretagogues)

Insulin release

Insulin release

Plasma Insulin (µU/mL)

The incretin effect**

Time (min) * Perley MI,et al. J Clin Invest. 1967; 46:1954-1962.

Plasma Insulin (µU/mL)

The incretin effect**

Time (min) * Perley MI,et al. J Clin Invest. 1967; 46:1954-1962.

Plasma Insulin (µU/mL)

The incretin effect* *

Time (min) * Perley MI,et al. J Clin Invest.

1967; 46:1954-1962.

Plasma Insulin (µU/mL)

The incretin effect**

Time (min) * Perley MI,et al. J Clin Invest. 1967; 46:1954-1962.

Incretin effect on insulin secretion People with Type 2 diabetes (n=14 (n=14 14))

80

80

60

60 Incretin effect

40 20

Insulin (mU (mU mU/l) /l)

Insulin (mU (mU mU/l) /l)

Control subjects (n=8 (n=8)

40 20 0

0 0

60

120

Time (min)

180

0

60

Time (min)

Nauck M, et al. Diabetologia. 1986

Oral glucose load Intravenous glucose infusion

120

180

Plasma Insulin (µU/mL)

And this finding

Time (min)

firmly implicated

gastrointestinal factors* as important mediators of

insulin secretion after oral glucose * Mcintyre N, et al. J Clin Endocrinol Metab , 1965 25 25::1317 1317– –1324 1324..

These factors have come to be termed

“Incretins Incretins““ (INtestine seCRETtion Insulin)

and their role on glucose homeostasis has led to

a novel class of incretin--based incretin antihyperglycemic agents based on the function and physiology of two endogenous dominant incretin hormones

These factors have come to be termed

“Incretins Incretins““ (INtestine seCRETtion Insulin)

and their role on glucose homeostasis has led to Zunz E, et al. Arch Int Physiol Biochim. 1929; 31: 20–44.

a novel class of incretin--based incretin antihyperglycemic agents based on the function and physiology of two endogenous dominant incretin hormones

The incretin hormones These two native incretin hormones are : Glucagon--like peptideGlucagon peptide-1 (GLP--1) (GLP Glucose--dependant Glucose insulinotropic peptide (GIP) that principally responsible for the incretin effect 1-8.

The incretin hormones These two native incretin hormones are : Glucagon--like peptideGlucagon peptide-1 (GLP--1) (GLP 1. Bell GI, et al. Nature 1983 ;302 :716 -718 2. Heinrich C. et al. Endocrinology 1984: 115:2176-2181 3. Mojsov S, et al. I Biol Chem 1986; 261:11880-11889 4. Novak U, et al. European Journal of Biochemistry 1987; 164:553-558 5. Holst JJ, et al. FEBS Lett 1987; 211:169-174 6. Kreymann B, et al. Lancet. 1987;2:1300-4 7. Ørskov C ,et al . Endocrinology 1986 ;119 :1467-1475 8. Mojsov S ,et al . J Clin Invest 1987; 79 :616-619

Glucose--dependant Glucose insulinotropic peptide (GIP)

that principally responsible for the incretin effect 1-8.

The incretin hormones

(K--cells of the intestinal mucosa) (K

 Glucose--dependant Glucose insulinotropic peptide (GIP) *

Takeda J, et al. Proc Natl Acad Sci U S A 1987; 84 84::7005 7005––7008

The incretin hormones (L--cells of the intestinal mucosa) (L

 

* Orskov C, et al. En- docrinology1986; 119 119::1467 1467— —1475 1475..

The incretin hormones  GLP-1 -secreting enteroendocrine L-cells are located predominantly in the ileum and colon1-3.  GIP-secreting enteroendocrine

K-cells are concentrated in the duodenum and proximal jejunum1-6. Plasma concentrations

Insulin

Plasma concentrations

GLP-1

Plasma concentrations

These native hormones are secreted at low basal levels in the fasting state and their circulating levels increase rapidly and transiently following food ingestion1-5 .

GIP

Hours

The incretin hormones  GLP-1 -secreting enteroendocrine L-cells are located predominantly in the ileum and colon1-3.  GIP-secreting enteroendocrine

K-cells are concentrated in 1.

Bell GI,et al. Nature 1983; 302: 716–718. Schmidt WE,et al. Diabetologia 1985; 28: 704–707. Kreymann B, et al. Lancet 1987; 2: 1300– 1304.

the duodenum and proximal jejunum1-6. Insulin

Plasma concentrations

These native hormones are secreted at low basal levels in the fasting state and their circulating levels increase rapidly and transiently following food ingestion1-5 .

GLP-1

Plasma concentrations

3.

Plasma concentrations

2.

GIP

Hours

The incretin hormones  GLP-1 -secreting enteroendocrine L-cells are located predominantly in the ileum and colon1-3.  GIP-secreting enteroendocrine

K-cells are concentrated in the duodenum and proximal jejunum1-6.

3. 4.

5.

6.

Plasma concentrations

2.

Inagaki N, et al. Mol Endocrinol 1989; 3: 1014–1021. Takeda J, et al. Proc Natl Acad Sci USA 1987; 84: 7005–7008. Brown JC, et al. J Physiol 1970; 209: 57–64. Dupre J, et al. J Clin Endocrinol Metab 1973; 37: 826–828. Adrian TE,et al. Diabetologia 1978; 14: 413–417. Taminato T, et al. Diabetes 1977; 26: 480– 484.

GLP-1

Plasma concentrations

1.

Insulin

Plasma concentrations

These native hormones are secreted at low basal levels in the fasting state and their circulating levels increase rapidly and transiently following food ingestion1-5 .

GIP

Hours

The incretin hormones  GLP-1 -secreting enteroendocrine L-cells are located predominantly in the ileum and colon1-3.  GIP-secreting enteroendocrine

K-cells are concentrated in the duodenum and proximal jejunum1-6.

These native hormones are secreted at low basal levels in the fasting state and their circulating levels increase rapidly and transiently following food ingestion1-5 . 4.

5.

Insulin

Plasma concentrations

3.

GLP-1

Plasma concentrations

2.

JF et al. Diabetes Metab 2005;31:233-242 Drucker DJ.Diabetes Care 2003; 26:1929-2940 Orskov C,et al. Diabetes 1994 ;43:535-53 Damholt, et al. Endocrinology 1999 ;140, 4800-4808 Holst, J. J. Physiol. Rev. 87: 1409-1439 2007; doi:10.1152/physrev.00034.2 006

Plasma concentrations

1.

GIP

Hours

Interactions between nutrients and GIP and GLPGLP- 1 On a rapid time scale, typically occurring when a meal is digested and absorbed,

nutrients and

the incretin hormones,GLP-1 and GIP,

Synergize in the acute stimulation of insulin secretion (exocytosis of insulin secretory granules) * *Jia X, et al . Am J Physiol 1995 ;268: E645–E651

Incretin receptors (GIP receptors) The human

gipr gene

1-4

 is localized to chromosome 19 19,, band q13 13..3.  is expressed in both α and β cells in pancreatic islets,  And in other tissues: GI tract, adipose tissue, adrenal cortex, pituitary, heart, testis, endothelium of major blood vessels, bone, trachea, spleen, thymus, lung, kidney, thyroid, and several brain areas.

Incretin receptors (GIP receptors) The human

gipr gene

1-4

 is localized to chromosome 19 19,, band q13 13..3.  is expressed in both α and β cells in pancreatic islets,  And in other tissues: GI tract, adipose tissue, adrenal cortex, pituitary, heart, testis, endothelium of major blood vessels, bone, trachea, spleen, thymus, lung, kidney, thyroid, and several brain areas. Dr. Abdulameer Abdullah Al- Ashbal ; Ass.Prof. , Consultant Diabetologist

Incretin receptors (GIP receptors) The human

gipr gene

1-4

 is localized to chromosome 19 19,, band q13 13..3.  is expressed in both α and β cells in pancreatic islets,  And in other tissues: GI tract, adipose tissue, adrenal cortex, pituitary, heart, testis, endothelium of major blood vessels, bone, trachea, spleen, thymus, lung, kidney, thyroid, and several brain areas. Dr. Abdulameer Abdullah Al- Ashbal ; Ass.Prof. , Consultant Diabetologist

Incretin Receptors (glp glp--1 Receptors) The human

glp--1r gene glp

1-5

 is located on chromosome 6p21 21..  Its genetic expression:  

may be almost exclusively restricted to the β cells and is present in cells lining the pancreatic ducts in a variety of other tissues: thyroid C cells, kidney, lung, heart, gastrointestinal track, skin, pituitary, and multiple regions of the peripheral and central nervous system.

Dr. Abdulameer Abdullah Al- Ashbal ; Ass.Prof. , Consultant Diabetologist

Incretin receptors (glp glp--1 receptors) The human

glp--1r gene glp

1-5

 is located on chromosome 6p21 21..  Its genetic expression:  

may be almost exclusively restricted to the β cells and is present in cells lining the pancreatic ducts in a variety of other tissues: thyroid C cells, kidney, lung, heart, gastrointestinal track, skin, pituitary, and multiple regions of the peripheral and central nervous system.

Molecular mechanisms underlying the insulinotropic effects of GIP and GLP-1 on Pancreatic beta cell* GIPR

Insulin

* Seino Y et al .J Diabetes Invest 2010,2040-1124)

GLP-1R

Mechanism of glucose-dependent, GLP-1-potentiated insulin secretion in the panvreatic β - cell

AC, adenylate cyclase; GLUT2, glucose transporter 2, PKA, protein kinase A.

Glucose-dependency of the insulin stimulatory effect of glucagon-like peptide-1* Insulin Release (% of total content)

10 mmol/L Glucose 2.8 mmol/L Glucose

GLP-1 (7-36) amide (pmol/L) *Goke R, et al. Res Exp Med (Berl). 1993; 193:97-103

Glucose-dependency of the insulin stimulatory effect of glucagon-like peptide-1* Insulin Release (% of total content)

10 mmol/L Glucose 2.8 mmol/L Glucose

2.8 mmol/L Glucose

GLP-1 (7-36) amide (pmol/L) *Goke R, et al. Res Exp Med (Berl). 1993; 193:97-103

Glucose-dependency of the insulin stimulatory effect of glucagon-like peptide-1*

Insulin Release (% of total content)

10 mmol/L Glucose 2.8 mmol/L Glucose

10 mmol/L Glucose

2.8 mmol/L Glucose

GLP-1 (7-36) amide (pmol/L) *Goke R, et al. Res Exp Med (Berl). 1993; 193:97-103

Summary of the incretin effect • Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) are the major incretin gut hormones released in response to food ingestion • GLP-1 and GIP enhance insulin secretion from β-cells in a glucose-dependent manner • GLP-1 suppresses glucagon release from α-cells in a glucose-dependent manner • The incretin effect is attributed to intestinal derived factors, GLP-1 and GIP • The incretin effect is diminished in Type 2 diabetes • GIP is not a therapeutic target: although its levels are normal in Type 2 diabetes, GIP is functionally ineffective Dr. Abdulameer Abdullah Al- Ashbal ; Ass.Prof. , Consultant Diabetologist

Recent hypothetical model for the acute and chronic effects of GLP--1 on pancreatic islets* GLP The acute postprandialmediated incretin effect would be mediated mainly by GLP-1 released from L cells acting locally and via portal release into the liver on neuronal activation.

Chronic trophic effects of GLP--1 on βGLP β-cells promoting survival and insulin production would be mediated via reprograming of the αα-cell by increasing the enzyme prohormone convertase PC11/3. PC

*

Donath MY , Burcelin R .GLP.GLP-1 Effects on Islets: Hormonal, Neuronal, or Paracrine Paracrine?? Diabetes Care 2013 ; 36 (Supplement 2): S145 S145 145--S148

Recent hypothetical model for the acute and chronic effects of GLP--1 on pancreatic islets* GLP The acute postprandialmediated incretin effect would be mediated mainly by GLP-1 released from L cells acting locally and via portal release into the liver on neuronal activation.

This would switch proglucagon processing from glucagon to GLPGLP-1 allowing for auto/paracrine auto/paracrine effects.

*

Donath MY , Burcelin R .GLP.GLP-1 Effects on Islets: Hormonal, Neuronal, or Paracrine Paracrine?? Diabetes Care 2013 ; 36 (Supplement 2): S145 S145 145--S148

Recent hypothetical model for the acute and chronic effects of GLP--1 on pancreatic islets* GLP The acute postprandialmediated incretin effect would be mediated mainly by GLP-1 released from L cells acting locally and via portal release into the liver on neuronal activation.

The trigger for this longlongterm adaptation could be IL--6 released by insulinIL insulinresistant fat tissues by contracting muscles or by insulitis as well as hyperglycemia. *

Donath MY , Burcelin R .GLP.GLP-1 Effects on Islets: Hormonal, Neuronal, or Paracrine Paracrine?? Diabetes Care 2013 ; 36 (Supplement 2): S145 S145 145--S148

Recent hypothetical model for the acute and chronic effects of GLP--1 on pancreatic islets* GLP

Accordingly, the main action of DPP-4 inhibition may occur at the tissue rather than at the plasma level

*

Donath MY , Burcelin R .GLP.GLP-1 Effects on Islets: Hormonal, Neuronal, or Paracrine Paracrine?? Diabetes Care 2013 ; 36 (Supplement 2): S145 S145 145--S148

Newly identified a local glucagonlike peptide 1 (GLP-1) system in human pancreatic islets

(Endocrine loop)

A local glucagon-like peptide 1 (GLP-1) system in human pancreatic islets (Endocrine loop)*

Studies have shown the presence of a functionally competent GLP-1 system in human pancreatic islets, which resides in alpha cells and might be modulated by type 2 diabetes.

* Marchetti P, et al. Diabetologia. 2012 Dec;55(12):3262-72. Ellingsgaard H, et al.Nat Med. 2011 Oct 30;17(11):1481-9. Whalley N M et al. J Endocrinol 2011;211:99-106.

A local glucagon-like peptide 1 (GLP-1) system in human pancreatic islets (Endocrine loop)*  IL-6 increased GLP-1 production from alpha cells through increased proglucagon and prohormone convertase 1/3 expression.  This newly identified endocrine loop implicates IL-6 in the regulation of insulin secretion and suggests that drugs modulating this loop may be useful in type 2 diabetes. *Ellingsgaard H, et al. Nat Med. 2011 Oct 30;17(11):1481-9

A local glucagon-like peptide 1 (GLP-1) system in human pancreatic islets (Endocrine loop)*  Proglucagon can be processed to GLP-1 in pancreatic cells. This process is upregulated by:    

Elevated glucose, Activation of G protein-coupled receptors TGR5 β-cell destruction. Understanding this phenomenon may lead to advances in therapies to protect β-cell mass, and thereby slow progression from insulin resistance to type 2 diabetes.

* Whalley N M et al. J Endocrinol 2011;211:99-106.

Expression of pancreatic islet proglucagon/proGLP-1 and prohormone convertases (PCs) in pancreatic α-cell lines*

* Whalley N M et al. J Endocrinol 2011;211:99-106

Sequences for prohormone convertases (qPCR)* Species Gene Hprt

Sequence Rat

Forward: CGAGCCGACCGGTTCTG Reverse: CATAACCTGGTTCATCATCACTAATCAC Probe: CATGTCGACCCTCAGTCCCAGCG

Mouse

Forward: GATTGTTGAAGATATAATTGACACTGGTAA Reverse: GGGTCCTTTTCACCAGCAAG Probe: CAAACTTTGCTTTCCCTGGTTAAGCAGTACAGC

Pc1

Rat

Mouse

Pc2

Rat

Mouse

Forward: TTTGCTCTAGCCTTGGAAGC Reverse: ATACTCAGAGGTCCAGACAACCAGA Probe: CCAAATCTCACCTGGCGAG Forward: TCTGGTTGTCTGGACCTCTGAGT Reverse: CAAGCCTGCCCCATTCTTT Probe: CGACCCATTGGCCAGTAACCCAGG Forward: GACCTGGCGAGACATGCAA Reverse: TGAAGCTGGTTTCGCTTGG Probe: ATCTGACAGTGCTCACC Forward: CACCTCCAAGCGGAACCA Reverse: GCCAAAGAGGTGATTAAATTCCA Probe: CCGTCGCCACTGATGAACCTCATCA

* Whalley N M et al. J Endocrinol 2011;211:99-106

Secretion of glucagon and GLP-1 from α-cells and islets in culture*

* Whalley N M et al. J Endocrinol 2011;211:99-106

Effect of glucose on prohormone convertases (PC1) in cultured islets*

* Whalley N M et al. J Endocrinol 2011;211:99-106

Secretion of glucagon and GLP-1 from α-cells and islets in culture*

* Whalley N M et al. J Endocrinol 2011;211:99-106

Expression and stimulation of L-cell GPCRs in αTC1-6 cells*

* Whalley N M et al. J Endocrinol 2011;211:99-106

β-Cell function in STZ-treated islets*

*Whalley N M et al. J Endocrinol 2011;211:99-106

Dipeptidyl--peptidase -IV (DPP -IV ) enzyme Dipeptidyl

A subset of prolyl oligopeptidases, including dipeptidyl-peptidase IV (DPP IV ) or CD26, specifically cleave off N-terminal dipeptides from substrates having proline or alanine in amino acid position 2.

Dipeptidyl-peptidase - 4 (DPP -IV ) enzyme*

In 1993 it was demonstrated that Dipeptidyl-peptidase - 4 (DPP -IV ) enzyme mediates the inactivation of

GLP-1 and GIP by removing the two N-terminal amino acids of the hormones. * Mentlein R, et al. Eur J Biochem 1993; 214:829–35. Bruckley D, et al Regul. Pept. 1992, 40, 117

Endocrine pathway for the actions of GLPGLP- 1* Nutrients in the gut lumen

Incretin Secretion L-cells cells-- intestinal villus 100% of the GLPGLP- 1 Luminal Endothelial cells DPP--IV** enzyme DPP Portal circulation (Liver) 25% 25 % of the GLPGLP- 1 Soluble plasma DPP--IV enzyme DPP Systemic circulation 10— 10 —15% of the GLPGLP- 1 Soluble plasma DPP--IV enzyme DPP The pancreas and the brain 10— 10 —15% or less of the GLPGLP- 1

* Holst J J,et al.Diabetologia 2005 48: 612-615

**DPP-IV:Dipeptidyl peptidase-IV

Inactivation of GLP-1 and GIP by Dipeptidyl peptidase-IV (DPP-IV) enzyme (1-11)

(Half-life of 1-1.5 min)

(Half-life of 7 min)

The inactivation enzyme

DPP-IV

(Half-life of 4-5 min)

(Half-life of 17 min)

Inactivation of GLP-1 and GIP by Dipeptidyl peptidase-IV (DPP-IV) enzyme (1-11)

(Half--life of 1-1.5 min) (Half

(Half-life of 7 min)

The inactivation enzyme

DPP-IV

(Half-life of 4-5 min)

(Half-life of 17 min)

GLP-1 (yellow) released by enteroendocrine L-cells * GLP-1 diffuses to the capillaries, where it is inactivated by DPP-4 enzyme (red)

GLP-1 GLP-1

* Histochemistry by C. Ørskov Ørskov,, the Panum Institute

The incretin hormones and Pathophysiology of Type 2 DM 1-12

In type 2 diabetes The secretion of

GIP

GLP--1 GLP

Normal or increased

reduced

The glucoseglucose-lowering actions of

GIP much weaker or absent (resistance)

GLP--1 GLP preserved

The incretin hormones and Pathophysiology of Type 2 DM 1-12

In type 2 diabetes The secretion of

GIP

GLP--1 GLP

Normal or increased

reduced

The glucoseglucose-lowering actions of

GIP much weaker or absent (resistance)

GLP--1 GLP preserved

The incretin hormones and Pathophysiology of Type 2 DM Consequently in patients with Type 2 diabetes, the incretin effect is either

abolished

or

severely reduced* (From normal 60 60% % to < 10 10%)** %)**

resulting in inappropriately low insulin secretion following oral ingestion of nutrients*. * Tronier B, et al . Diabetes Clin Pract1985;[Suppl 1]:S568. Nauck M , et al. Diabetologia 1986;29:46-52. Diabet Med 2000;17:713–719.

** Mentlein R, et al. Eur J Biochem 1993; 214: 829–35. Rask E, et al. Metabolism 2004; 53 : 624 –631.

Pathophysiological changes in Type 2 diabetes1-6

Type 2 diabetes

Pathophysiological changes in Type 2 diabetes1-6

Type 2 diabetes

Decreased insulin secretion

Pathophysiological changes in Type 2 diabetes1-6

Increased Insulin resistance

Decreased insulin secretion

Type 2 diabetes

Pathophysiological changes in Type 2 diabetes1-6 Increased hepatic glucose production Increased Insulin resistance

Decreased insulin secretion

Type 2 diabetes

Pathophysiological changes in Type 2 diabetes1-6 Increased hepatic glucose production Increased Insulin resistance

Decreased insulin secretion

Increased glucagon secretion

Type 2 diabetes

Pathophysiological changes in Type 2 diabetes1-6 Increased hepatic glucose production Increased Insulin resistance

Decreased insulin secretion

Increased glucagon secretion

Type 2 diabetes

Deranged adipocyte biology

Pathophysiological changes in Type 2 diabetes1-6 Increased hepatic glucose production Increased Insulin resistance

Decreased insulin secretion

Increased glucagon secretion

Type 2 diabetes

Deranged adipocyte biology

Increased gastric-emptying rate

Pathophysiological changes in Type 2 diabetes1-6 Increased hepatic glucose production Increased Insulin resistance

Decreased insulin secretion

Increased glucagon secretion

Type 2 diabetes

Deranged adipocyte biology

Increased gastric-emptying rate

Impaired incretin effect 1. Decreased secretion of GLP-1 2. Impaired response to GIP

Pathophysiological changes in Type 2 diabetes1-6 Increased hepatic glucose production Increased Insulin resistance

Decreased insulin secretion

Increased glucagon secretion

Type 2 diabetes

Deranged adipocyte biology

Increased gastric-emptying rate

Impaired incretin effect 1. Decreased secretion of GLP-1 2. Impaired response to GIP

The unique antidiabetic effects of Glucagon-like peptide-1 The lost efficacy of GIP

precludes its application as a therapeutic agent. While the preserved effect of GLP- 1

has inspired attempts to treat Type 2 diabetes with it * ‫٭‬Hoist II, et al ? Bio Drugs 2002 2002;; 16 16::175 175--181

Approaches to enhance incretin effects The preserved effects of GLPGLP- 1 has inspired attempts to treat Type 2 diabetes with it 1-4 Because GLP GLP--1 is rapidly inactivated by the enzyme DPP DPP--4, modulating its

Level & activity has become a major focus of investigation for treating type 2 diabetes by one of major three approaches, which are known as

GLP--1 - based therapies GLP or incretin - based therapies

Approaches to enhance incretin effects The preserved effects of GLPGLP- 1 has inspired attempts to treat Type 2 diabetes with it 1-4 Because GLP GLP--1 is rapidly inactivated by the enzyme DPP DPP--4, modulating its

Level & activity has become a major focus of investigation for treating type 2 diabetes by one of major three approaches, which are known as

GLP--1 - based therapies GLP or incretin - based therapies

Therapeutic effect of GLPGLP-1 in people with Type 2 diabetes Glucose (mmol/l)

C-peptide (nmol/l)

17..5 17

Glucagon (pmol/l)

3 .0

30

GLP--1 infusion GLP

GLP--1 infusion GLP

GLP--1 infusion GLP

15

2 .5 12..5 12

* * *

2 .0 10

*

7.5

*

5

*

*

GLP--1 GLP Saline

2.5

0

60

*

120

180

*

15

1 .0

10

*

0 .5

5

240

0 .0 –30

*

0

–30

20

1 .5

*

25

* * *

0

Time (min)

*P