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1、INSULIN RESISTANCE AND BETA CELL DYSFUNCTION: A DYNAMIC DUET RESPONSIBLE FOR T2DM,Ralph A. DeFronzo, MD Professor of Medicine Chief, Diabetes Division UTHSC, San Antonio, TX,TREATMENT OF T2DM: A SOUND APPROACH BASED UPON ITS PATHOPHYSIOLOGY,Ralph A. DeFronzo, MD Professor of Medicine Chief, Diabetes
2、 Division UTHSC, San Antonio, TX,THE TRIUMVIRATE,Impaired Insulin Secretion,Hyperglycemia,Decreased Glucose Uptake,Increased HGP,DeFronzo RA, Diabetes 37:667-687, 1988,NATURAL HISTORY OF BETA CELL FAILURE IN T2DM,Beta cell failure occurs much earlier in the natural history of type 2 diabetes and is
3、more severe than previously appreciated,SAN ANTONIO METABOLISM AND VAGES STUDIES,SUBJECTS NUMBER NGT 318IGT 259T2DM 201,Gastaldelli, Ferrannini, Abdul-Ghani, DeFronzo, Diabetologia 47:31-39, 2004; JCEM 90:493-500, 2005, Diabetes 55:1430-35, 2006,METHODS: OGTT and Insulin Clamp,PLASMA GLUCOSE AND INS
4、ULIN AUC,Glucose AUC (mmol/L120 min),Insulin AUC (pmol/L120 min),INSULIN SECRETION / INSULIN RESISTANCE (DISPOSITION) INDEX DURING OGTT, INS/ GLU IR,Lean,2-Hour PG (mg/dl),FASTING PLASMA GLUCOSE (FPG) CONCENTRATION AND RELATIVE BETA CELL VOLUME IN OBESE SUBJECTS WITH NGT, IFG, & T2DM,Butler et al, D
5、iabetes 52:102-110,2003,FPG (mg/dl),-cell Volume (%),SUMMARY,Are maximally/near-maximally insulin resistant Have lost 80% of their beta cell function (DeFronzo) Have lost significant beta cell mass (Butler) Have an incidence of diabetic retinopathy of 10%,Individuals with IGT:,PREVENTION OF BETA CEL
6、L FAILURE IN T2DM,Must intervene early (IGT/IFG),Interventions should target pathogenic mechanisms known to promote beta cell failure and cause insulin resistance,Decreased Incretin Effect,Decreased Insulin Secretion,Increased,HGP,Isleta cell,Increased Glucagon Secretion,OMINOUS OCTET,Increased,Lipo
7、lysis,Increased Glucose Reabsorption,Decreased Glucose Uptake,Diabetes 58:773-795, 2009,TREATMENT OF T2DM,(1) Will require multiple drugs in combination to correct multiple pathophysiologic defects (2) Should be based upon known pathogenic abnormalities, and NOT simply on the reduction in HBA1c (3)
8、Must be started early in the natural history of T2DM, if progressive beta cell failure is to be prevented,Hyperglycemia,TREATMENT OF TYPE 2 DIABETES: A SOUND APPROACH BASED UPON ITS PATHOPHYSIOLOGY,Impaired Insulin Secretion,Hyperglycemia,Decreased Glucose Uptake,Increased Lipolysis,TZDs,GLP-1 analo
9、gues,Increased HGP,UKPDS 352:837-853 and 853-865, 1998,EXCESS GLYCEMIC BURDEN,-2,-1,0,1,Change in HbA1c (%),TIME (years),0,1,2,3,4,5,6,10,Hanefeld (n=250),Charbonnel (n=313),Chicago (n=230),ADOPT (n=1,441),UKPDS (n=1,573),Gliclazide,PERISCOPE (n=181),GLY,Glimepiride,Glyburide,Glyburide,Glyburide,Gly
10、buride,SU,SU,Alvarsson (n=39),Alvarsson (n=48),RECORD (n=272),Tan (n=297),Gliclazide,DURABILITY OF GLYCEMIC CONTROL WITH SULFONYLUREAS,-2,-1,0,1,Change in HbA1c (%),TIME (years),0,1,2,3,4,5,6,PIO,PIO,Rosiglitazone,DURABILITY OF GLYCEMIC CONTROL WITH THIAZOLIDINEDIONES,Hanefeld (n=250),Charbonnel (n=
11、317),Chicago (n=232),ADOPT (n=1,456),PIO,PERISCOPE (n=178),PIO,RECORD (n=301),Rosenstock (n=115),ROSI,Tan (n=249),PIO,PLEIOTROPHIC EFFECTS OF TZDs,Insulin sensitivity Insulin secretion Lipotoxicity Dyslipidemia Atherosclerotic CVD NASH Nephropathy,EFFECT OF THIAZOLIDINEDIONES ON INSULIN-MEDIATED GLU
12、COSE DISPOSAL,mg/kg FFMmin,Before,PIO,ROSI,0,4,6,8,10,*,*,NOGD,GOX,EFFECT OF PIOGLITAZONE (6 MONTHS) ON INSULIN SENSITIVITY, PLASMA FFA, MUSCLE FAT (MRS) AND FACoA CONTENT IN TYPE 2 DIABETIC SUBJECTS,0,4,8,12,16,0,1,2,0.4,0.5,0.6,0.7,0,Rd (mg/kg min),Plasma FFA (mg/L),Muscle Fat (%),Muscle LC-FACoA
13、(mmol/g),PRE,POST,PRE,POST,PRE,POST,4,8,PRE,POST,*,*,*,*,Baja & DeFronzo, unpubl. obs,EFFECT OF TZD AND PLACEBO TREATMENT ON ISR IN RELATIONSHIP TO INSULIN RESISTANCE, ISR (AUC), Glucose (AUC),1 IR,x,Nave + Placebo,Nave + PIO,Nave + ROSI,SU + Placebo,SU + PIO,*,*,*,Before Rx After Rx,THIAZOLIDINEDIO
14、NES AND PRESERVATION OF BETA CELL FUNCTION,Direct effect on the beta cell (PPARg) Amelioration of insulin resistance Reduction in plasma FFA (lipotoxicity) Mobilization of toxic lipid metabolites (FACoA, DAG, ceramides) out of the beta cell (lipotoxicity) Reversal of glucotoxicity,LIPOTOXICITY, INSU
15、LIN RESISTANCE, AND ASCVD,Elevated plasma FFA Increased tissue fat content Altered fat topography Adiposopathy,LIPOTOXICITY PLAYS A CENTRAL ROLE IN THE PATHOGENESIS OF T2DM,Increased FFA,Increased HGP,Decreased Glucose Uptake,Kashyap et al, Diabetes 52:2461-68, 2003 Thiebaud et al, Metabolism 21:1128-36, 1982,LIPOTOXICITY,Elevated plasma FFA Increased tissue fat content Altered fat topography Adiposopathy,Arterial Fat,
