RESISTIN

DR KINZA SAMMAR

OBJECTIVES•DEFINE•ORIGIN•ACTIONS•RELATIONS

CONTENTS • INTRODUCTION• DEFINITION• DISCOVERY• MECHANISM OF ACTION• RELATIONS WITH LIVER, DIABETES AND OBESITY• FUNCTIONS• SUMMARY• REFRENCES

INTRODUCTION :

• RESISTIN IS AN ADIPOSE-DERIVED HORMONE (SIMILAR TO A CYTOKINE) WHOSE PHYSIOLOGIC ROLE HAS BEEN THE SUBJECT OF MUCH CONTROVERSY REGARDING ITS INVOLVEMENT WITH OBESITY AND DM .

WHAT IS RESISTIN ???• RESISTIN IS A PROTEIN-BASED HORMONE PRODUCED BY FAT CELLS.

• ITS NAME IS BASED ON ITS REPUTATION FOR CAUSING THE CONDITION OF “INSULIN RESISTANCE” WHEN INTRODUCED INTO ANIMALS.

• ADIPOCYTES SECRETE A UNIQUE SIGNALLING MOLECULE, WHICH WE HAVE NAMED RESISTIN (FOR RESISTANCE TO INSULIN).

ADIPOCYTES AND DERIVATIVES :

DEFINITION “ CYSTEINE-RICH ADIPOSE-DERIVED PEPTIDE HORMONE.”• RESISTIN ALSO KNOWN AS ADIPOSE TISSUE-SPECIFIC SECRETORY FACTOR .

• FAT CELLS IN MICE ALSO SECRETE A SMALL PROTEIN (108 AMINO ACIDS) CALLED RESISTIN.

STRUCTURE

•THE LENGTH OF THE RESISTIN PRE-PEPTIDE IN HUMAN IS 108 AMINO ACID RESIDUES.

•THE MOLECULAR WEIGHT IS ~12.5 KDA

STRUCTURE • CRYSTAL STRUCTURES OF RESISTIN.• HEXAMER-FORMING DISULFIDE BONDS. • SUBUNITS THAT ARE HELD TOGETHER BY NON-

COVALENT INTERACTIONS THAT MAKE UP ITS STRUCTURE…

SECRETION • IN PRIMATES, PIGS, AND DOGS, RESISTIN IS SECRETED BY IMMUNE AND EPITHELIAL CELLS.

• IN RODENTS, IT IS SECRETED BY ADIPOSE TISSUE.

LINK WITH LIVER,CHOLESTEROLAND HEART :

• RESISTIN HAS BEEN SHOWN TO CAUSE "HIGH LEVELS OF 'BAD' CHOLESTEROL (LOW-DENSITY LIPOPROTEIN OR LDL), INCREASING THE RISK OF HEART DISEASE.

• RESISTIN INCREASES THE PRODUCTION OF LDL IN HUMAN LIVER CELLS.• AS A RESULT, THE LIVER IS LESS ABLE TO CLEAR 'BAD' CHOLESTEROL

FROM THE BODY. • RESISTIN ACCELERATES THE ACCUMULATION OF LDL IN ARTERIES,

INCREASING THE RISK OF HEART DISEASE. • RESISTIN ADVERSELY IMPACTS THE EFFECTS OF STATINS, THE MAIN

CHOLESTEROL-REDUCING DRUG USED IN THE TREATMENT AND PREVENTION OF CARDIOVASCULAR DISEASE.

ACTIONS OF RESISTIN :• RESISTIN CAUSES TISSUES — ESPECIALLY THE LIVER — TO

BE LESS SENSITIVE TO THE ACTION OF INSULIN, WHICH IS THE HALLMARK OF TYPE 2 DIABETES.

• BLOOD GLUCOSE LEVELS RISE BECAUSE OF INCREASED GLYCOGENOLYSIS AND GLUCONEOGENESIS IN THE LIVER.

• IN HUMANS, RESISTIN IS PRIMARILY A PRODUCT OF MACROPHAGES, NOT FAT CELLS. NEVERTHELESS, THERE IS A STRONG ASSOCIATION IN HUMANS BETWEEN ELEVATED LEVELS OF RESISTIN, OBESITY, AND TYPE 2 DIABETES (OVER 80% OF THE PEOPLE WITH TYPE 2 DIABETES ARE OBESE).

RESISTIN AND INSULIN RESISTANCE:• BASED ON ANIMAL RESEARCH, RESISTIN IS HYPOTHESIZED

TO BE A CAUSE OF REDUCED INSULIN SENSITIVITY IN HUMANS.

• IN A REVIEW PUBLISHED IN THE APRIL 2004 ISSUE OF THE “JOURNAL OF INTERNAL MEDICINE,” SYNTHETICALLY MADE INSULIN ADMINISTERED TO RODENTS “CAUSED INSULIN RESISTANCE BY INCREASING LIVER GLUCOSE PRODUCTION AND INHIBITING INSULIN-STIMULATED GLUCOSE UPTAKE AT FAT CELLS AND SKELETAL MUSCLE.”

• Like many hormones, resistin operates at multiple body tissues, including skeletal muscle, liver and adipose.

• Because of its capacity to interfere with insulin’s activity in animals, investigation is under way to unearth a correlation between resistin and type 2 diabetes in humans.

HIGH FAT DIET :

RESISTIN AND DIABETES :

TYPE 2 DIABETES IS CAUSED BY AN INABILITY OF INSULIN TO MOVE GLUCOSE INTO CELLS.

INSULIN RESISTANCE IS THE HALLMARK OF TYPE 2 DIABETES AND IS MANIFESTED ALL OVER THE BODY.

• DESCRIBED AS POOR INSULIN SENSITIVITY IN WHICH TARGET CELLS “RESIST” PROPER INSULIN FUNCTION, RESULTING IN DISEASE.

RESISITIN AND ANTI DIABETIC DRUGS :• RESEARCH PUBLISHED IN THE DECEMBER 2003 ISSUE OF “THE

JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM” INVOLVING ANTI-DIABETIC DRUGS CALLED THIAZOLIDINEDIONES (WHICH ENHANCE INSULIN SENSITIVITY) SHOWED THAT RESISTIN WAS SUPPRESSED BY THE DRUG IN RODENTS, SUGGESTING A CORRELATION BETWEEN THE PRESENCE OF RESISTIN AND INSULIN OPERATION.

• THE SAME STUDY REVEALED THAT RESISTIN CAUSED A “MODEST CONCENTRATION-DEPENDENT IMPAIRMENT OF GLUCOSE METABOLISM IN HUMAN ADIPOSE CELLS.”

• RESISTIN IS HYPOTHESIZED TO INTERFERE WITH INSULIN’S ABILITY TO INSTIGATE A CHANGE WITHIN THE CELLULAR MACHINERY SO AS TO PROPERLY DISPOSE OF GLUCOSE FROM THE BLOODSTREAM.

LINK BTW DIET AND DIABETES :• WHILE TYPE-1 DIABETES IS UNRELATED TO DIET, SCIENTISTS

HAVE LONG DISCOVERED A CONNECTION BETWEEN SUGAR INTAKE AND THE INCIDENCE OF TYPE-2 DIABETES.

• WHEN YOU CONSUME TOO MUCH ADDED SUGAR, THE PANCREAS RELEASES LARGE AMOUNTS OF A HORMONE CALLED INSULIN TO REMOVE THE SUGAR FROM YOUR BLOODSTREAM.

• CONSUMING EXCESS SUGAR REGULARLY CAN SET OFF A CASCADE OF METABOLIC DISTURBANCES, INCLUDING INSULIN RESISTANCE, WHICH EVENTUALLY CAN LEAD TO TYPE-2 DIABETES.

RESISITIN AND OBESITY :

SERUM RESISTIN LEVELS WILL INCREASE WITH INCREASED ADIPOSITY.

SPECIFICALLY, CENTRAL OBESITY (WAISTLINE ADIPOSE TISSUE) SEEMS TO BE THE FOREMOST REGION OF ADIPOSE TISSUE CONTRIBUTING TO RISING LEVELS OF SERUM RESISTIN.

ROLE IN INFLAMMATION : IT ALSO PARTICIPATES IN THE INFLAMMATORY RESPONSE.

• INFLAMMATION IS THE FIRST INNATE IMMUNE RESPONSE TO INFECTION OR IRRITATION RESULTING FROM LEUKOCYTE (NEUTROPHILS, MAST CELLS, ETC.) ACCUMULATION AND THEIR SECRETION OF INFLAMMATORY, BIOGENIC CHEMICALS SUCH AS HISTAMINE, PROSTAGLANDIN, AND PRO-INFLAMMATORY CYTOKINES.

• RESISTIN WAS FIRSTLY PROPOSED TO BE INVOLVED IN INSULIN RESISTANCE AND TYPE 2 DIABETES. RECENTLY, IT WAS FOUND TO BE RELEVANT TO INFLAMMATION AND INFLAMMATION-RELATED DISEASES LIKE ATHEROSCLEROSIS AND ARTHRITIS.

INFLAMMATION CONT.

• AN INCREASED EXPRESSION OF SEVERAL PRO-INFLAMMATORY CYTOKINES INCLUDING (BUT NOT LIMITED TO) INTERLEUKIN-1 (IL-1), INTERLEUKIN-6 (IL-6), INTERLEUKIN-12 (IL-12), AND TUMOR NECROSIS FACTOR-Α (TNF-A)

INFLAMMATORY ROLE :• IT HAS PROINFLAMMATORY PROPERTIES.• ABUNDANT IN INFLAMMATORY CONDITIONS LIKE ARTHRITIS,

• IN HUMAN, RESISTIN IS EXPRESSED IN INFLAMMATORY CELLS , LEUCKOCYTES AND MACROPHAGES.

DETECTION OF RESISTIN LEVEL :

• SANDWICH ENZYME LINKED IMMUNOASSAY.

• PLASMA LIPOPROTEINS• TOTAL CHOLESTEROL• HDL• LDL

REFRENCES :

• LU SC, SHIEH WY, CHEN CY, HSU SC, CHEN HL (OCTOBER 2002). "LIPOPOLYSACCHARIDE INCREASES RESISTIN GENE EXPRESSION IN VIVO AND IN VITRO". FEBS LETT. 530 (1–3): 158–62. DOI:10.1016/S0014-5793(02)03450-6. PMID 12387885.

• JUMP UP ^ WELLEN KE, HOTAMISLIGIL GS (MAY 2005). "INFLAMMATION, STRESS, AND DIABETES". J. CLIN. INVEST. 115 (5): 1111–9. DOI:10.1172/JCI25102. PMC 1087185. PMID 15864338.

• JUMP UP ^ WULSTER-RADCLIFFE MC, AJUWON KM, WANG J, CHRISTIAN JA, SPURLOCK ME (APRIL 2004). "ADIPONECTIN DIFFERENTIALLY REGULATES CYTOKINES IN PORCINE MACROPHAGES". BIOCHEM. BIOPHYS. RES. COMMUN. 316 (3): 924–9. DOI:10.1016/J.BBRC.2004.02.130. PMID 15033490.

• JUMP UP ^ YOKOTA T, ORITANI K, TAKAHASHI I, ISHIKAWA J, MATSUYAMA A, OUCHI N, KIHARA S, FUNAHASHI T, TENNER AJ, TOMIYAMA Y, MATSUZAWA Y (SEPTEMBER 2000). "ADIPONECTIN, A NEW MEMBER OF THE FAMILY OF SOLUBLE DEFENSE COLLAGENS, NEGATIVELY REGULATES THE GROWTH OF MYELOMONOCYTIC PROGENITORS AND THE FUNCTIONS OF MACROPHAGES". BLOOD 96 (5): 1723–32. PMID 10961870.

• JUMP UP ^ AXELSSON J, BERGSTEN A,