The Regulation of Insulin Secretion Through Adipokines
The regulation of insulin secretion through adipokines
Sunmin Park
Dept. of Food and Nutrition Hoseo University Relationship of insulin action and insulin secretion in type 2 diabetes
Hyper Western Hypoglycemia type 2 DM High
Asian Normal Serum Normal type 2 Glucose DM Glucose Intolerance Low Insulin Secretion Type 2 Mody No IR None Type 1 None Reduced Normal Extreme Insulin Action Type 2 diabetes results from Multi system defects
Skeletal Muscles Adipose Liver β Cell Brain
Common defects: insulin/IGF 1 signaling
Peripheral Hepatic Insulin Hyperphagia, Insulin Action Glc Prod Secretion & IR, hepatic β cell mass Glc prod
Type 2 Diabetes Insulin/IGF 1 and leptin signaling
Insulin/IGF 1 Leptin receptor Receptor
PI 3,4 PI,4 P pY SHIP2 P2 PH PTB pY PI3,4,5 P3 PI 4,5 P2 pY pY pY PTP1B STAT3 PTEN PI 3 kinase Grb2/SOS SHP2
ras raf MEK MAPK mTOR PDK1 PDK2 PHAS p90 RSK p70 S6K PKC ζ/PKC λ PKB/akt FKHR L1(P) FKHR(P) eIF4 GSK3 BAD FKHR L1FKHR L1 FKHRAPX HNF3 elk1 fos
Protein Glucose Glycogen Cell Gene Synthesis Transport Synthesis Survival Transcription
hypothalamaus Food intake, hepatic glucose output, insulin secretion Regulate energy and glucose homeostasis in peripheral tissues through brain
Autonomous nerve system and neurotransmitters Adipokines, gut hormones, insulin Adipokines secreted from white adipose tissues Adipokine neurons distributed in the hypothalamus
PVN : paraventriclular nucleus DMH: Dorsomedial hypothalamic nucleus VMH: Ventromedial nucleus ARC: Arcuate nucleus LHA:Lateral hypothalamic area Long term energy balance via brain
Sympathetic nerve or Vagus nervous system
Badman MK & Flier JS. Science, 2005 Roles of adipokines : energy homeostasis
ICV injection Visceral fat: Leptin Visfatin ? Visfatin ? How do adipocytes interact with islets? • Functional interaction of adipokines and β cell function and β cell mass – Direct adipokine effects – Indirect adipokine effects through autonomous nervous system The adipoinsular axis to control energy and glucose homeostasis Hypothalamus: Modulation of leptin, Insulin, and AMPK signaling adiopokines euglycemia Kieffer TJ & Hanener JF. Am J Physol Endocrin Metab, 2000 Circuit of white adipose tissue and islets into CNS (Fliers E et al. J Neuroendo, 2003) DMN: brainstem nucleus SCN: suprachiasmatic nucleus IML: internal medullary lamina Activation of sympathetic nervous system ( )to release noradrenaline, galanin and NPY : inhibit basal and glucose stimulated insulin secretion; stimulate glucagon secretion Activation of parasympathetic nervous system ( ) to release acetylcholin, VIP, PACAP, gastrin releasing hormones (GRP) : stimulate insulin and glucagon secretion ICV adipokines and β cell function and mass • ICV leptin, resistin, and leptin+resistin • ICV adiponectin • ICV leptin with/without sympathetic nervous system into the pancreas Characteristics of 90% pancreatectomized rats • 90% pancreatectomized rats (partial pancreatectomized rats): – After removing 90% of the pancreas, it regrows up to 40 50% of the intact pancreas within 2 weeks from the surgery. – β cell mass : about 50 60% of the Sham non diabetic rats since β cell density of Px rats is greater than Sham rats – Insulin secretion : about 50 60% of Sham rats, in parallel with β cell mass – Insulin resistance: gradually exacerbated after removal of the pancreas and a high fat diet accelerates insulin resistance – Non obese • Asian type 2 diabetes: – Non obese – No hyperinsulinemia usually have normoinsulinemia or hypoinsulinemia – Increased insulin resistance 90% pancreatectomzed rat is a good animal model for Asian type 2 diabetes. ICV leptin and resistin effect on glucose metabolism Park S et al. Endocrinology, 2008 Potential action of leptin on hypothalamus Via ANS DMV IML Badman MK & Flier JS. Gastroenterology, 2007 Action mechanism of resistin ? ? (Stofkova A. Endocrine Regul, 2010) Experimental design 0 1 2 5 6 weeks Purchase Px ICV Leptin, resistin Catheter Hyperglycemic 219 ±12g leptin+resistin, CSF insertion clamp Male rats infusion via osmotic pump BrdU (80 ng/day leptin clamp injection 2 ug/day resistin) Serum leptin and resistin levels CSF Leptin Resistin Lep+Res 7 120 a 6 a a a* 100 5 b b b* 80 4 c 60 3 40 2 Serum leptin (ng/mL) 1 Serum resistin (ng/mL) 20 0 0 *Significantly different among the groups at p<0.05. a,b,c Means of the bars with different superscripts were significantly different Leptin and insulin signaling in the hypothalamus CSF Leptin Res Lep+Res Leptin Resistin IB: pSTAT 3 IB: STAT 3 IB: pAMPK pSTAT3 pSTAT3 IB: AMPK pAMPK pAMPK IP: IRS2 pyIRS2 pyIRS2 IB: py20 pAKT pAKT IP: IRS2 IB: IRS2 IB: pAkt IB: Akt Glucose tolerance 30 CSF Leptin Resistin Lep+Res 25 ** ** ** 20 * ** *** 15 10 5 Serum glucose (mM) 0 0 10 20 30 40 50 60 70 80 90 100 110 120 TIme (min) 5 CSF Leptin Resistin Lep+Res a 4 b 3 b b* (ng/mL) 2 a Serum insulin b b b* 1 0 0 min 40+60 min 90+120 min Insulin secretion during hyperglycemic clamp CSF Leptin Resistin Lep+Res 7 6 * * 5 * 4 * 3 2 1 Serum insulin (ng/mL) * 0 0 10 20 30 40 50 60 70 80 90 100 110 120 Time (min) *Significantly different among the groups at p<0.05. Insulin sensitivity at hyperglycemic state CSF leptin Res Lep+Res 45 a 40 a* 35 30 b 25 20 c a a 15 b 10 c 5 0 Glucose infusion rate (mg/kg Insulin sensitivity ( mol bw/min) glucose min 1 100 g 1 per mol insulin/L) a,b,c Means of the bars with different superscripts were significantly different β cell area and mass 50 CSF leptin Res Lep+Res a 40 b* 30 c c CSF 20 a b* 10 c c 0 β cell area (%) β cell mass (mg) a,b,c Means of the bars with different superscripts Resistin were significantly different β cell proliferation 2.5 2 a a* 1.5 b b Cont 1 of islets) 0.5 BrdU+ cells (% BrdU+ cells 0 CSF leptin Res Lep+Res a,b,c Means of the bars with different superscripts Resistin were significantly different β cell apoptosis 2 a 1.5 ab b* 1 Cont islets) c 0.5 Apoptosis (% apoptotic bodies of 0 CSF leptin Res Lep+Res a,b,c Means of the bars with different superscripts were significantly different Resistin Summary • Both central leptin and resistin improved glucose tolerance. – ICV leptin inhibited insulin secretion but potentiated insulin sensitivity at hyperglycemic state. – ICV resistin improved first phase insulin secretion and increased β cell mass. – The combination of ICV leptin+resistin have additive and complementary effects. ICV leptin effect on glucose metabolism through sympathetic nervous system Park S et al. Life Sci, 2010 Long-term ICV leptin on glucose metabolism 0 1 2 3 6 7 weeks Purchase Px SNS ICV Leptin Catheter BrdU 212 ±18g denervation CSF injection insertion injection Male rats ICV implantation via osmotic pump Hyperglycemic (1 ug /day) clamp SNS denervation in pancreas (SNSX) : By chemical (phenol) application in the descending aorta between kidney and pancreas. Leptin signaling in the hypothalamus SNSX C SNSX L Sham C Sham L Leptin w/o SNS Leptin Tyr705 pSTAT 3 STAT 3 Thr172 pAMPK pSTAT3 AMPK pAMPK Glucose tolerance SNSX C SNSX L Sham C Sham L 25 * * * * * 20 * ** 15 10 5 *Leptin effect at P<0.05 Serum glucose (mM) †SNS effects at P<0.05 0 0 10 20 30 40 50 60 70 80 90 100 110 120 Time (min) 10 SNSX C SNSX L Sham C Sham L a a a 8 6 b* † a a a a a b* † 4 b b* 2 0 AUC of glucose (AU) AUC of insulin (0 50min) AUC of insulin (50 120 min) Insulin secretion during hyperglycemic clamp SNSX C SNSX L Sham C Sham L 9 8 *† *† *† 7 *† 6 5 *† 4 3 2 1 Serum insulin (ng/mL) 0 0 10 20 30 40 50 60 70 80 90 100 110 120 Time (min) *Significant effect of leptin at p<0.05. †Significant effect of denervation of sympathetic nervous system into the pancreas (SNSX) at p<0.05 . Insulin sensitivity at hyperglycemic state SNSX C SNSX L Sham C Sham L 25 20 a a* † 15 a b b a* † 10 b b 5 0 Glucose infusion rate (mg/kg Insulin sensitivity ( mol glucose bw/min) min 1 100 g 1 per mol insulin/L) *Significant effect of leptin at p<0.05. †Significant effect of denervation of sympathetic nervous system into the pancreas (SNSX) at p<0.05 . β cells in the pancreas Small β cell cluster Small β cell cluster Duct SNSX C SNSX L associated single β cells and β cell buds Duct Duct associated Small β cell single β cells and cluster β cell buds Sham C Sham L Summary • Central leptin inhibited insulin β cell function through sympathetic nervous system. • However, β cell mass was not modulated by central leptin. • Denervation of sympathetic nervous system into the pancreas did not affect insulin sensitivity at hyperglycemic state. ICV adiponectin effect on glucose metabolism Park S. et al. J Neuroendocrinology 2011 Adiponectin action mechanism ? ? Yamauchi T & Kadowaki T. Int J Obesity 2008 Adiponectin and obesity R2 R1 ? (Ahima & Lazar. hypothalamus Food intake Mol Endocrin, 2008) Adiponectin effect on AMPK Adiponectin ( g/mL) 0 0.3 1.5 4.5 In L6 myotubes For 30 min treatment pAMPK of adiponectin AMPK 0 1 2 5 6 weeks Purchase Px ICV adiponectin Catheter Hyperglycemic 221 ±14g infusion via insertion clamp Male rats osmotic pump BrdU (1.2 ug /day) injection Serum and CSF adiponectin levels Sham CSF Sham ADP Px CSF Px ADP 300 8 a a a*† 7 a b 250 6 b b c*† 200 5 c*† d 4 150 3 100 b c 2 50 1 0 0 Serum leptin (ng/mL) Serum adiponectin CSF adiponectin (ng/mL) ( g/mL) *Significant effect of adiponectin (ADP) at p<0.05. †Significant effect of diabetic status at p<0.05. Leptin and insulin signaling in the hypothalamus Sham CSF Sham ADP Px CSF Px ADP pSTAT3 pAMPK pSTAT3 py20 IRS2 pAMPK pAkt pyIRS2 β actin pAKT Glucose tolerance Sham CSF Sham ADP Px CSF Px ADP 25 *† *† *† *† 20 *† *† *† 15 *† *† † 10 † 5 Serum glucose (mM) 0 0 10 20 30 40 50 60 70 80 90 100 110 120 Time (min) 350 Sham CSF Sham ADP Px CSF Px ADP a 300 a 250 a 200 b b† (AU) b b*† 150 c 100 Area under the curve 50 0 Glucose Insulin Insulin secretion during hyperglycemic clamp Sham CSF Sham ADP Px CSF Px ADP 8 † † 7 † 6 *† 5 *† *† 4 3 *† 2 1 Serum insulin (ng/mL) 0 0 10 20 30 40 50 60 70 80 90 100 110 120 Time (min) *Significant effect of adiponectin (ADP) at p<0.05. †Significant effect of diabetic status at p<0.05. Insulin sensitivity at hyperglycemic state Sham CSF Sham ADP Px CSF Px ADP 25 a a 20 b b b*† 15 c c*† 10 d 5 0 Glucose infusion rate (mg/kg Insulin sensitivity ( mol bw/min) glucose min 1 100 g 1 per mol insulin/L) *Significant effect of adiponectin (ADP) at p<0.05. †Significant effect of diabetic status at p<0.05. β cell area and mass Sham CSF Sham ADP Px CSF Px ADP 50 45 a 40 b 35 30 c*† 25 d 20 15 *† b a 10 c b 5 0 β cell area (%) Absolute β cell mass (mg) *Significant effect of adiponectin (ADP) at p<0.05. †Significant effect of diabetic status at p<0.05. β cell proliferation and apoptosis Sham CSF Sham ADP Px CSF Px ADP 1.4 1.2 a* a a 1 b*† b b b 0.8 c 0.6 0.4 0.2 0 BrdU+ cells (% BrdU+ cells of Apoptosis (% apoptotic bodies of islets) islets) *Significant effect of adiponectin (ADP) at p<0.05. †Significant effect of diabetic status at p<0.05. Summary • Central adiponectin did not improve β cell function but it increases β cell mass by decreasing β cell death. • Central adiponectin also enhanced insulin sensitivity at hyperglycemic state. Serum adipokines in GDM patients Glucose Profiles Normal weight (BMI<23) Overweight (BMI>=23) Non GDM GDM Non GDM GDM (n=395) (n=98) (n=136) (n=117) Fasting Glucose 78.8 ±5.4 c 84.9 ±8.4 b 80.2 ±4.9 bc 92.8 ±12.4 a*† (mg/dL) Glucose at 1 h after 111.0 ±14.7 b 163.5 ±17.5 a 113.1 ±14.4 b 169.0 ±26.1 a*† 50 g glucose (mg/dL) Fasting Insulin ( U/mL) 11.6 ±5.6 c 11.1 ±3.7 c 12.8 ±5.8 b 15.7 ±6.2 a*† b a b a* HbA 1C (%) 5.3 ±0.3 5.8 ±0.4 5.4±0.4 5.8 ±0.5 HOMA IR 2.1 ±1.0 d 2.3 ±0.9 c 2.5 ±1.2 b 3.6 ±1.6 a*† HOMA B 293.7 ±229.2 a 197.7 ±86.6 b 288.7 ±153.5 a 219.1 ±129.9 b* Circulating adipokine profiles NRW Non GDM NRW GDM OVW non GDM OVW GDM 16 14 a 12 a† a 10 8 b b a a b 6 b c* b b* 4 a* † 2 a b † a † c c b b a a b c* 0 Adiponectin Adipsin Leptin Resistin Visfatin CRP ( g/mL) ( g/mL) (ng/mL) (ng/mL) (ng/mL) (mg/mL) *Significantly different by gestational diabetes (GDM) at P<0.05 †Significantly different by body mass index (BMI) at P<0.05 a,b,c Means in the same row with different superscripts were significantly different Conclusions Adipokines regulates β cell function and mass as well as insulin sensitivity through several signal pathways including autonomic nervous system. Roles of adipokines glucose homeostasis in diabetic rats β cell mass Glucose tolerance : Leptin, adiponectin, resistin similar Visfatin ? Adipokines regulate insulin secretion and insulin resistance via sympathetic nerves and vagus nervous system Visfatin ? Possible sympathetic and parasymthathetic neural pathways to stimulate insulin secretion ( B. Diabetologia, 2000)