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A brief report. Zeynep Oşar Istanbul Univ. Cerrahpaşa Medical Faculty Division for Endocrinology, Metabolism and Diabetes. Topics summarized. I ncretin biology Their role of in the treatment of type 2 diabetes mellitus . GLP1 and incretin biology. Type 2 diabetes-advances in therapy.

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a brief report

A brief report

Zeynep Oşar

Istanbul Univ. Cerrahpaşa Medical Faculty

Division for Endocrinology, Metabolism and Diabetes

topics summarized
Topics summarized
  • Incretin biology
  • Their role of in the treatment of type 2 diabetes mellitus
incretins
Incretins
  • The hormonal factorsimplicated as transmitters of signalsfrom the gut to pancreatic beta-cells
  • Secondary control system of glucose homeostasis after meal intake
  • GIP & GLP1 members of the glucagon peptide superfamilyand share considerable aminoacid identity.
incretins6
42 amino acid peptide

Released from duodenal and proximal jejunal K cells

NH2 terminal inactivation by

DPP-4

30/31 aminoacid peptide

Released from L cells in distal small bowel and colon

NH2 terminal inactivation by

DPP-4

Incretins

GIP

GLP1

Drucker DJ. Diabetes Care 2003.

incretin receptor a g protein coupled receptor
GIPR

Islet ß-cells

Adipose tissue

Osteoblasts

CNS

GLP1-R

Islet - and ß-cells

CNS

Periperal NS

Heart

Kidney

Lung

Gastrointestinal tract

Incretin receptor: A G-protein coupled receptor
postreceptor pathways
Postreceptor pathways
  • GIP secreted from gut after nutrient stimulus
  • Stimuli other than nutrients (neural or endocrine)

in GLP-1 secretion?

  • Receptor interaction
  • Activated beta cell signalling pathways: cAMP (MAP kinase, PI3-kinase/protein kinase B?)
  • Increase in ic. Ca
  • Stimulation of insulin secretion

Visboll T et al. Diabetologia 2004;47:357–366.

actions
Stimulates insulin secretion

Promotes expansion of beta cell mass

Minimal effect on gastric emptying

No effect on glucagon secretion

Normal GIP secretion in diabetic subjects

Defective GIP reponse in type 2 DM

Stimulates insulin secretion

Expansion of B cell mass

Inhibits gastric emptying

Inhibits glucagon secretion

Inhibits food intake and weight gain

Reduced GLP-1 secretion in T2DM

Preserved GLP-1 reponse in type 2 DM

Actions

GIP

GLP1

insulin levels after glucose challenge in gipr deficient mice
Insulin levels after glucose challenge in GIPR deficient mice

Plasma insulin (pg/ml))

*

*

Time (min)

Miyavaki K et al. Proc Natl Acad Sci 1999; 96:14843–14847.

plasma glucose excursions after glucose chalenge in gipr deficient mice
Plasma glucose excursions after glucose chalenge in GIPR deficient mice

*

*

Blood glucose (mg/dl)

Time (min)

Miyavaki K et al. Proc Natl Acad Sci 1999; 96:14843–14847.

slide13

Additive effects of GLP-1 and GIP on insulin secretionBasal and peak plasma insulin levels after oral glucose load in male WT, Glp-1R–/–,Gipr–/–, and double-KO mice

##

§

§§

Plasma İnsulin (ng/ml)

Time (min)

##p<0.01 vs double KO

§ p< 0.005 vs. double KO

§§ p< 5 × 10–4 vs. WT controls

Preitner F et al. J Clin Invest 2004; 113:635–645.

glp 1 improves beta cell survival and mass
Modulation of ER stress

Increased levels of cAMP, Akt, and IRS

Reduced expression and reduced activation of effector caspases

Decreased glucolipotoxicity

Adaptation to metabolic and cellular stress

Prevention of beta cell apoptosis & proliferation

Upregulation of expression of genes (glucokinase, GLUT 2)

Increased mitotic activity

Promotes differentiation of duct progenitor cells

GLP-1 improves beta cell survival and mass

Drucker D et al. C Met 2006;4:391–406.

effects beyond incretin17
Effects beyond incretin
  • GIPR on adipocytes
    • Stimulation of LPL
    • Fat accumulation (Role in obesity?)
  • GIPR on osteoblasts
    • Ca accumulation
    • Inhibition of apoptosis in osteoblast
    • Increased osteoblastic activity
    • Increased bone mineral density

Yamada Y et al. Diabetes 2006;55 (Suppl. 2):S86–S91.

Miyawaki K et al. Proc Natl Acad Sci 1999; 96:14843–14847.

acronym gip
Acronym GIP =
  • Gastric inhibitory polypeptide
  • Glucose dependent insulinotropic polypeptide
  • Gut derived nutrient intake polypeptide

Yamada Y et al. Diabetes 2006;55 (Suppl. 2):S86–S91.

targets of glp 1
Targets of GLP-1
  • Hepatoportal sensors
  • Nervous system
the effects glp 1 on hepatoportal sensors
The effects GLP-1 on hepatoportal sensors

L cells

GLP1

Peripheral

circulation

Portal

circulation

Sensor+GLUT2

&

GLP1-R

Beta cells

&

GLPR

Stimulation of

glucose utilization

Burcelin R et al. Diabetes 50:1720–1728, 2001

brain glp 1 and its effects
Brain GLP-1 and its effects
  • GLP1 secretion from cerebral cells in nucleus tractus solitarius and area postrema
  • Activation of cerebral GLP1-R
  • Sympatethic stimulation and increase in BP and HR
  • Regulation of food and water intake
  • Extrapancreatic regulation of glucose metabolism
    • Inhibited muscle glucose utilization
    • Increased insulin secretion and increased insulin resistance to favor hepatic glycogen storage

Knauf C et al. J Clin Invest 2005; 115:3554–3563.

slide23

Normalization of fasting hyperglycaemia by exogenous glucagon-like peptide 1 (7-36 amide) in type 2 (non-insulin-dependent) diabetic patients.

Nauck MA et al.

Diabetologia 1993. 36:741-744.

glp1 agonists
GLP1 agonists
  • Exenatide
  • Liraglutide
  • Exenatide LAR
dpp4 inhibitors
DPP4 Inhibitors

(DPP4 is a serine protease, bound to endothelial

membranes or in the soluble form)

  • Vildagliptin
  • Sitagliptin
  • Saxagliptin
  • Denagliptin

(Non-selectivity for actions on the related enzymes

DPP-8, DPP-9)

Lankas G et al. Diabetes 2004; 54: 2988 –94.

Nauck M et al. Diabetologia 2005; 48: 608–11.

exenatide 1
Exenatide-1
  • Naturally occurring GLP1-related peptide isolated from the venom of the lizard Heloderma suspectum
  • 50% homology with mammalian GLP1
  • Potent degradationresistant agonist of GLP1
  • Circulating half life of 60-90 min
  • Duration of action lasts 4-6 h

Drucker D. JClin Invest 2007; 117: 24-31

exenatide 2
Exenatide-2
  • 5-10 g sc injections twice daily
  • Postprandial glucose control
  • HbA1c reductions of 0.8-1.0% in combination with OAD
  • Prevention of weight gain or weight loss of 1-3 kg
  • Adverse events:Nausea, vomiting, diarrhoea, hypoglycemia,antibody formation

DeFronzo RA et al. DiabetesCare 2005; 28: 1092–00.

Kendall DM et al. Diabetes Care2005; 28: 1083–91.

liraglutide
Liraglutide
  • A DPP-4-resistant GLP-1 analogue
  • Non-covalent binding to albumin
  • Half-life 10–14 h
  • A once daily sc. Injection up to 0.75 mg-2 g daily
  • Reduces fasting andpostprandial glucose
  • Reduction in HbA1c by up to 1.75 %
  • Weight neutral or modest weight loss
  • Nausea, vomiting,and diarrhoea

Drucker D. JClin Invest 2007; 117: 24-31

dpp4 inhibitors30
DPP4 Inhibitors
  • Reduced DPP4 activity by more than 80% maintained for 24 h withonce daily treatment
  • Vildagliptin 100mg od and Sitagliptin 100mg od as effective as rosiglitazone inmonotherapy, significant reductions in HbA1c combinationwith metformin
  • Adverse effects: No significant hypoglycaemia or weight gain
  • Inhibition of lymphocyte proliferation ?
  • Fewer data for saxagliptin and denagliptin

Raz I et al. Diabetologia2006; 49: 2564–71.

Garber A et al. Diabetes 2006;55 (suppl 1): 29.

contrasting actions of glp1 r agonsits and dpp4 inhibitors
Contrasting actions of GLP1-R agonsits and DPP4 inhibitors

Drucker D. JClin Invest 2007; 117: 24-31

summary
Summary
  • The incretins are hormonal factors regulating postprandial glucose metabolism.
  • They increase beta cell mass.
  • GIP is an obesity promoting factor and increases bone mass.
  • Brain GLP-1 has a role in controlling whole-body and tissue-specificglucose metabolism in hyperglycemic conditions.
  • The available evidence strongly suggests that drugs having incretinomimetic actions are promising alternatives for the treatment of type 2 diabetes mellitus.