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The Regulation of Insulin Secretion Through Adipokines

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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 Insulin Secretion Type 2 Mody No IR No 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<resistin<adiponectin IP injection Visfatin ? Visfatin ? How do adipocytes interact with islets? • Functional interaction of adipokines and βcell function and βcell 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 pancreaswithin 2 weeksfrom the surgery. – β-cell mass: about 50-60% of the Sham non-diabeticratssince β-cell density of Px ratsisgreater 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 acceleratesinsulin 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) glucose Serum 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 insulinSerum b b 1 b* 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) Serum * 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 (µmol bw/min) glucose min-1 100 g-1 per µmol 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) of 0.5 BrdU+ cells (% (% 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 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) glucose Serum †SNS effectsat 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 (µmol glucose bw/min) min-1 100 g-1 per µmol 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 (µg/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) (µg/mL) *Significant effect of adiponectin (ADP) at p<0.05.
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