IN THE NAME OF GOD A 41 yrs. old Lady – - PowerPoint Presentation

1. IN THE NAME OF GODA 41 yrs. old Lady – known case of Lipodystrophy Referred for Pre LiverTx Evaluation due to Hepatic Cirrhosis 1Presentation By Dr. Ali Golshaian9th Khordad 1401

2. Patients ID:41 yrs. old woman Born & live in GhaemshahrMarried – One childMaster of Science of Physical (Sport) EducationWorking in Athletic Club 2

3. Chief Complaint:She is referred for pre liverTx surgery evaluation due to hepatic cirrhosis She is known case of Lipodystrophy since ~20 y ago3

4. Present Illness: At early Esfand 1400, She discomfort from Abdominal dull (Periumbilical) non-specific pain.At evaluation Hepatic Cirrhosis was appeared. She was candidate for Liver Transplantation, so for per-Tx work up refereed to Endocrinology clinic.4

5. Past medical and Drug history:Probably Trigger DisorderAcromegaloid featureDiabetes MellitusCirrhosisNephropathyMenstruation PregnancyOther Complications5

6. Past medical and Drug history:Probably Trigger DisorderShe was a white, thin & mediocre girl with special food habits:She avoided Fatty foods, she hasn`t still eaten butter & cream. At 3rd year of guidance school, at 14 yrs. old; after a mountain climbing, She felt Generalized Paralysis with severe muscular pain specially at extremities. Insomnia & Morphine use due to her pain was occurred.Her paralysis lasted for 1 month, then after she could do her personal activity, But her muscular pain & numbness in extremities lasted for 1 year.Absolute Diagnosis & treatment hasn`t yet demonstrated.DDx:Viral Myelitis Autoimmune Disorder6

7. Past medical and Drug history:Acromegaloid featureAbout years 1374 - 76 (High School period) at age: 15 – 17:She manifested these features gradually:Tall stature (?) (Gigantism) / Hand & Foot Enlargement (Shortening of shoe size) / Frontal bossing / Prominent Nose / Ear EnlargementShe has been at average length in early high school (~1.5 m), But she became the tallest student at late high school (~1.7 m). 7

8. Past medical and Drug history:Acromegaloid featureAlso as in available documents were noted, these features were seen:Acanthosis Nigricans, Decreased fat tissue at face & trunk No consanguinity between Mother & Father.Tall stature (?) (Gigantism)Patient Height: 173cm (All↓: Oral document)Mother Height: 165cm Father Height:168cm MPH: Sons: 173 ± 10 Daughters: 160 ± 8.5Brothers: 184 , 158 Sisters: 163 , 1538

9. Past medical and Drug history:Acromegaloid featureShe & her family didn`t notice at these acromegaloid features.After determining her DM, about age 19-20 yrs. old; Her acromegaloid feature is considerated. She under investigated several times and laboratory exams and imaging were done frequently with suspicion to Acromegaly. She was known as a case of “Acromegaly” at that time due to her clinical appearance but any laboratory data and imaging did not approve it.9

10. Past medical and Drug history:Acromegaloid featureIn available documents:1383.02.05: 0,30,60,90,120 min: Glu: 125>225>198>225>258 GH: 0.5>1.9>0.61>0.75>0.1 1384.05.18OGTT 100 g – Glu: 88 > 192 > 294 GH: 1.7 ng/ml > 0.4 > 3.61385.02.31IGF: 450 ng/ml (in Normal range;140-644) But at Oral document: More than 10 times she has evaluated for Acromegaly, even once sending laboratory tests to Germany. All were normal.10

11. Past medical and Drug history:Acromegaloid featureIn available documents: 83.4.3: MRI A faint hypointense mass in the pituitary gland on the left side without any mass effect on the optic chiasma.84.5.20: MRI Convexity of upper pituitary surface with thickened pituitary stalk But at Oral document: These two MRI revising showed no significant point, Also, MRI repeated over 10 times, All seemed be normal.11

12. Past medical and Drug history:Diabetes MellitusYear 1377; At 3rd year of high school, at 17 yrs. old; She found Polydipsia, Polyuria, Weight loss (~6 Kg), abnormal fatigue & appetite increasing after exercise for 1 year and her Diabetes Mellites was appeared (Her sister became nursing student at that time).Glibenclimide was begun for paitent.Year 1379-80; At Age 19-20 yrs. Old, 4 years after acromegaloid features, 2 years after DM: Because of continuing of symptoms & uncontrolled BSs, She met endocrinologist:Oral agent (Metformin) + Insulin (NPH & Reg) were begun. 12

13. Past medical and Drug history:Diabetes MellitusIn available documents:1385.06.07 (Admission at Taleghani Hospital) Hb: 13.3 PLT: 196000 Ca: 9.5 P: 5.5 Cr: 0.8 76 u 50 uInsulin NPH: Reg: 64 u 26 u13FBSHbA1CCholTGHDLLDL879.622023057127

14. Past medical and Drug history:Diabetes MellitusAbout years 86-87; gradually dose of insulin received to 1500 units / day during 2 – 3 years. Morning & Evening: NPH 400 u + Reg 360 u sc (?) {26 vials NPH, 24 vials Reg}Insulin pomp was proposed, But due to Cost, she couldn’t provide it.Despite of insulin using her BSs didn`t meet Nl (~upper 300)Then because of Painful Injections, She discontinued insulin, arbitrary.Amenorrhea/Oligomenorrhea + Hepatic steatosis + Diabetic Nephropathy was emerged at that time that will discuss later.14

15. Past medical and Drug history:Diabetes MellitusShe continued her treatment with (About years 87-68) :Metformin 4 g / day at start >>> 2 g / day at nowPioglitazone 30 mg / day >>> 45 mg / DayAt this time BSs achieved controlled range. This treatment has continued until now (except in pregnancy) 1401.01.22: FBS: 174 1401.02.11: HbA1c: 7.5%Also, at that time, she hes been used: Omega 3 (?) + Gemfibrozil 300mg/day & then Fenofibrate 200/day (for recent 5 years), Also Livergol & Inderal was prescripted for her since year 1387.15

16. Past medical and Drug history:Cirrhosis About years 86-87 :Impaired LFT: AST,ALT ~ 100-200 (Oral document)Sonography: Hepatic steatosis , Splenomegaly (Oral document)Endoscopy & Colonoscopy: NL (Oral document)Liver Biopsy: ? (Oral document)Patient was observed by multiple Gastroenterologist & Livergol & Inderal was prescripted for her. At early Esfand 1400, She discomfort from Abdominal dull (Periumbilical) non-specific pain.16

17. Past medical and Drug history:Cirrhosis Esfand 1400:1401.01.22 AST: 26 ,ALT: 24, Alkp: 88, δGT: 69 (7-32), Alb: 4.9PT: 14.7, PTT: 30.7, INR: 1.05, αFP: 2.6 Sonography 1401.01.23: Coarse echo, Normal size, Port 11mm, Splenomegaly (153 mm)Endoscopy & Colonoscopy: GUD (underwent treatment), others NlFibroscan: The median liver fibrosis was 23 Kpa which is F4Patient was candidated for Liver Tx.17

18. Past medical and Drug history:Nephropathy 1385.06.07 (Admission at Taleghani Hospital)1385.06.07 Cr: 0.8Sonography 1385.06.12: Both kidney: Large size; Rt: 133*39mm, Lt: 145*51mm Nl Parenchymal Echo & measurement, Prominent Medulla due to Diabetic NephropathyAbout years 86-87:Proteinuria > 1 gr/day (Oral document)Liver Biopsy: Diabetic Nephropathy (Oral document)Year 95: Proteinuria > 2 gr/day (Oral document)During Pregnancy Proteinuria achieved > 10 gr/day18

19. Past medical and Drug history:Hypertriglyceridemia 1385.06.07 (Admission at Taleghani Hospital)About year 90: TG > 1000, Chol ~ Nl (Oral document)Fat restricted regimen, Also Omega 3 (?) + Gemfibrozil 300mg/day & then Fenofibrate 200/day (for recent 5 years) continued. 1401.01.2219FBSHbA1CCholTGHDLLDL879.622023057127FBSHbA1CCholTGHDLLDL17418222142105

20. Past medical and Drug history:MenstruationPuberty: Such as another girlsMenstruation: Oligomenorrhea – sometimes Massive BleedingYear 1382-85; At Age 23-26 yrs. Old, For about 3 or 4 years Amenorrhea manifested.LD was begun.She married at 1394.LD discontinued >>> 1397 : Pregnancy 20

21. Past medical and Drug history:PregnancySBP: 130 – 140She underwent Insulin therapy (~ 150 u/day with controlled BSs)She hospitalized form pregnancy 4th month to 7th month.Proteinuria achieved > 10 gr/dayEvery other day sonography and another tests for evaluation of fetus health was done.She underwent C/S at 7th month.Son neonate (Kian) had 2800 gr at birth and discharged at first day.Mother was underobserved in ICU for 1 week after.Neonate was admitted for jaundice 1 week later.21

22. Past medical and Drug history:Other ComplicationsAt year 1392: She underwent two surgeries:? / Vitrectomy due to Retinal detachment (Diabetic Retinopathy) (Oral document)Carpal tunnel syndrome surgery (Rt Hand)22

23. Habitual History: Neg Social History : NegFamily History : Neg23

24. Review of Systems:Gigantism / Hand & Foot Enlargement / Frontal bossing / Prominent Nose / Ear Enlargement No fat tissue in skin folds; trunk, face, extremesMasculinized bodyHeadache (-) Nausea & Vomiting (-) Visual problems (-)Weight changes (-) Appetite changes (-) Skin: Pigmentation (±) Diaphoresis (-) Acanthosis nigricans (-)Cardiovascular: Nl, Palpitation (-) Respiratory: NlGastrointestinal: Nl, Musculoskeletal: NlNeurological: Nl24

25. Physical Examination:GENERAL APPEARANCE: 41 yrs. old woman , awake and alertVital Sign:BP: 120/80 mmHgHR: 80 / min 25

26. Physical Examination:Acromegaliod feature: Gigantism / Hand & Foot Enlargement / Frontal bossing / Prominent Nose / Ear Enlargement No fat tissue in skin folds; trunk, face, extremesThorax: NlLungs : ClearHeart : Normal Abdomen : No striaeSkin: No pigmentationExtremities : Upper : Normal, No abnormal enlargement Lower : Normal, No abnormal enlargement26

27. PROBLEM LIST A 41-year-old woman known case of Lipodystrophy referred for pre liverTx evaluation due to hepatic cirrhosisAt 14 yrs. old; She felt Generalized Paralysis with severe muscular pain At age: 15–17; She manifested Acromegaloid featuresAt 17 yrs. old; her Diabetes Mellites was appearedGradually dose of insulin received to 1500 units/day because of Painful Injections, She discontinued insulin.Metformin & Pioglitazone started & BSs achieved controlled rangeCirrhosis / Diabetic Nephropathy / Retinopathy / HyperTGOligomenorrhea, Amenorrhea / Complicated Pregnancy27

28. Lipodystrophy28

29. AGENDA29

30. AGENDACase PresentationLipodystrophy OverviewClassification of Lipodystrophic syndromesPathophysiology of LipodystrophyMechanism responsible for severe insulin resistanceFat Redistribution and Fat Metabolism Adipocytokines Inflammation: TNF-α / IL6Endoplasmic Reticulum and Mitochondrial Stress Insulin resistance & Acromegaloid feature Treatment of syndromes of lipodystrophies Lifestyle ModificationManagement of Insulin Resistance Management of DyslipidemiaManagement of Cosmetic Appearance Adipokines in Lipodystrophy30

31. AGENDACase PresentationLipodystrophy OverviewClassification of Lipodystrophic syndromesPathophysiology of LipodystrophyMechanism responsible for severe insulin resistanceFat Redistribution and Fat Metabolism Adipocytokines Inflammation: TNF-α / IL6Endoplasmic Reticulum and Mitochondrial Stress Insulin resistance & Acromegaloid feature Treatment of syndromes of lipodystrophies Lifestyle ModificationManagement of Insulin Resistance Management of DyslipidemiaManagement of Cosmetic Appearance Adipokines in Lipodystrophy31

32. Lipodystrophy OverviewThe lipodystrophic states are a diverse group of clinical disorders: Congenital / AcquiredComplete / Partial (lipoatrophy / lipohypertrophy) Insulin resistance and its associated clinical featuresSevere hyperlipidemiaProgressive hepatic steatosis ¹Although lipodystrophy syndromes have been considered as ultra-rare diseases, with a prevalence of less than 5 cases per million, they are largely underdiagnosed, and systematic genetic screening suggests that 1/7000 individuals could be affected. ² 321: (2016) De Groot J, Larry Jameson MD PhD Leslie J, Endocrinology Adult & Pediatric 7th Edition P: 648,6492: (2022) Zammouri J, et al. Molecular and Cellular Bases of Lipodystrophy Syndromes. Front Endocrinol (Lausanne). 2022 Jan 3;12:803189. doi: 10.3389

33. Lipodystrophy OverviewGeneralized Lipodystrophies: CGL:Congenital Generalized Lipodystrophy or Berardi-nelli-Seip congenital lipodystrophy (BSCL), is a rare syndrome characterized by near-complete absence of body fat. Autosomal recessive / Parental consanguinity The first 2 years of life and frequently soon after birthAdipose tissue is absent from subcutaneous & intraabdominal sites but a prominent fatty liver, and presence of fat in certain anatomic sites such as orbits, palms, and soles. 33(2016) De Groot J, Larry Jameson MD PhD Leslie J, Endocrinology Adult & Pediatric 7th Edition P: 649,650

34. Lipodystrophy OverviewCongenital Generalized Lipodystrophy:Children with CGL tend to have voracious appetite and an accelerated growth; precocious menarche and/or pubarche, signaling early puberty, are rarely observed. Insulin resistance has been noted at an early age and may be present even at birth. It is usually refractory to insulin therapy. Diabetic complications of nephropathy, retinopathy, acute pancreatitis, and hepatic steatosis are typically present and are a major cause of morbidity.Serum adipocytokines, the hormones produced by adipose tissue (such as leptin and adiponectin), circulate in extremely low levels in CGL. 34(2016) De Groot J, Larry Jameson MD PhD Leslie J, Endocrinology Adult & Pediatric 7th Edition P: 649,650

35. Lipodystrophy OverviewCongenital Generalized Lipodystrophy:CGL 1: AGPAT2 gene mutations ›› AGPAT2 (1-acylglycerol-3-phosphate O-acyltransferase 2) which catalyzes the acylation of lysophosphatidic acid to phosphatidic acid ↓ metabolically important adipose tissue & ↑ mechanically important adipose tissueCGL 2: BSCL2 gene mutations ›› Seipin may include adipocyte differentiation / Related to more severe adipose tissue loss than in CGL1 / Higher incidence of premature death / Higher prevalence of intellectual impairment ↓ metabolically important adipose tissue & ↓ mechanically important adipose tissueCGL 3CGL 435(2016) De Groot J, Larry Jameson MD PhD Leslie J, Endocrinology Adult & Pediatric 7th Edition P: 650,651

36. 36(2022) Zammouri J, et al. Molecular and Cellular Bases of Lipodystrophy Syndromes. Front Endocrinol (Lausanne). 2022 Jan 3;12:803189. doi: 10.3389

37. 37(2020) Williams Textbook of Endocrinology, 14th edition P:1585Phospholipid and triglyceride synthesis: Glycerol-3-phosphate is converted by glycerol- 3-phosphate acyltransferases (GPATs) to lysophosphatidic acid, which is converted to phosphatidic acid by acylglycerol-phosphate acyltransferases (AGPATs). Phosphatidic acid can be converted to cytidine diphosphate diacylglycerol (CDP-DAG), to fuel one arm of phospholipid synthesis, or to diacylglycerol (DAG), which is a substrate for another arm of phospholipid synthesis and for acyl-CoA: diacylglycerol acyltransferases (DGATs), which generate triglycerides.

38. Lipodystrophy OverviewGeneralized Lipodystrophies: Acquired Generalized Lipodystrophy: Also known as Lawrence syndrome, it develops in a previously healthyindividual, often after a nonspecific febrile illness. Generalized loss of fat (Retroorbital and bone marrow fat may be preserved)Childhood and adolescence – F/M : 3/1 – WhiteThe median time to develop DM after loss of fat tissue is approximately 4 years. Hypertriglyceridemia, hepatic steatosis, acanthosis nigricans, menstrual irregularities, and polycystic ovary syndrome (PCOS)Markedly reduced adiponectin / moderately reduced leptin38(2016) De Groot J, Larry Jameson MD PhD Leslie J, Endocrinology Adult & Pediatric 7th Edition P: 651

39. Lipodystrophy OverviewAcquired Generalized Lipodystrophy: Several autoimmune diseases and inflammatory conditions have shown a temporal relationship to AGL. These include juvenile-onset dermatomyositis (JDM), rheumatoid arthritis, systemic sclerosis, systemic lupus erythematosus, Sjögren syndrome, and panniculitis. JDM shows a particularly strong correlation with lipodystrophy; 8% to 40% of patients with JDM develop acquired lipodystrophy. AGL following autoimmune diseases is also termed AGL type 2 or the autoimmune disease variety. 39(2016) De Groot J, Larry Jameson MD PhD Leslie J, Endocrinology Adult & Pediatric 7th Edition P: 651

40. Lipodystrophy OverviewAcquired Generalized Lipodystrophy: Panniculitis is another inflammatory condition that frequently heralds the onset of AGL. It is estimated to be present in approximately 25%.The panniculitis variety is also known as AGL type 1. Up to 50% of AGL patients have no clear history of autoimmune disease or panniculitis.These lipodystrophies are known as AGL type 3 or the idiopathic type. 40(2016) De Groot J, Larry Jameson MD PhD Leslie J, Endocrinology Adult & Pediatric 7th Edition P: 651

41. Lipodystrophy OverviewPathophysiology of Lipodystrophy:The adipocyte lipid droplet is able to store excess energy as triglycerides in the postprandial state.Adequate storage of energy in adipocytes protects other organs from lipotoxicity due to lipid overload, which leads to oxidative stress, mitochondrial dysfunction, apoptosis and tissue dysfunction ¹Adipose tissue is an endocrine gland that secretes numerous factors, affecting energy homeostasis, insulin sensitivity, and nutrient-sensing pathways:Leptin / Adiponectin / TNF-α ²411: (2022) Zammouri J, et al. Molecular and Cellular Bases of Lipodystrophy Syndromes. Front Endocrinol (Lausanne). 2022 Jan 3;12:803189. doi: 10.33892: & Figure: (2016) De Groot J, Larry Jameson MD PhD Leslie J, Endocrinology Adult & Pediatric 7th Edition P: 642

42. Lipodystrophy OverviewLeptin Leptin crosses the blood-brain barrier and serves as a signal to thecentral nervous system >> ↓ Food intake, ↑ Energy expenditure ¹Leptin regulates satiety by acting on hypothalamic neurons, and modulates carbohydrate and lipid metabolism by acting on muscle, liver adipose tissue and pancreatic beta-cells. Leptin deficiency increases appetite, which worsens metabolic profile. Integrated effects of leptin ensure an efficient protection of non-adipose tissues from lipid accumulation. ²421: (2016) De Groot J, Larry Jameson MD PhD Leslie J, Endocrinology Adult & Pediatric 7th Edition P: 643,6442: (2022) Zammouri J, et al. Molecular and Cellular Bases of Lipodystrophy Syndromes. Front Endocrinol (Lausanne). 2022 Jan 3;12:803189. doi: 10.3389

43. Lipodystrophy OverviewLeptin Leptin concentrations are positively correlated with body fat mass The asymmetric biological effect of leptin: Low levels of circulating leptin trigger strong biological responses to protect the organism against the deleterious effect of starvation, whereas high levels of leptin (as seen in obesity) engender rather weak biological responses.The reduction in leptin with starvation caused a decrease in the activity of the gonadal and thyroid axes and an increase in the activity of the adrenal axis. 43(2016) De Groot J, Larry Jameson MD PhD Leslie J, Endocrinology Adult & Pediatric 7th Edition P: 642,643

44. Lipodystrophy OverviewAdiponectinAdiponectin is inversely related to fat mass How the increased mass of the tissue from which the gene is expressed reduces expression and/or secretion, is still an unanswered question.Adiponectin is clearly an insulin-sensitizing hormone.Lipodystrophic patients have very low concentrations of adiponectinReduction in circulating adiponectin (as well as leptin) may facilitate the ectopic storage of fat. 44(2016) De Groot J, Larry Jameson MD PhD Leslie J, Endocrinology Adult & Pediatric 7th Edition P: 644,645

45. Lipodystrophy OverviewFree fatty acidsIncreased lipid fluxes activate hepatic production of VLDL, triglycerides and glucose, and impair muscular glucose uptake.Redistribution of body fat, withalso contributes to metabolicdysfunction. ¹451: (2022) Zammouri J, et al. Molecular and Cellular Bases of Lipodystrophy Syndromes. Front Endocrinol (Lausanne). 2022 Jan 3;12:803189. doi: 10.3389Figure: (2016) De Groot J, Larry Jameson MD PhD Leslie J, Endocrinology Adult & Pediatric 7th Edition P: 643

46. Lipodystrophy OverviewRedistribution of body fat, with increased visceral fat and decreased subcutaneous fat, particularly of the lower limbs, also contributes to metabolic dysfunction. Subcutaneous adipose tissue is physiologically more sensitive to insulin. It has been shown that subcutaneous adipose tissue of the lower part of the body is protective against diabetes and cardiovascular diseases in the general population.Conversely, visceral adipose tissue is more sensitive than subcutaneous adipose tissue to adipocyte lipolysis. Furthermore, visceral adipose tissue directly releases fatty acids into the portal vein, which are captured by the liver, leading to an increased risk of liver lipotoxicity, liver steatosis and insulin resistance. 46(2022) Zammouri J, et al. Molecular and Cellular Bases of Lipodystrophy Syndromes. Front Endocrinol (Lausanne). 2022 Jan 3;12:803189. doi: 10.3389

47. Lipodystrophy OverviewVisceral fat is more susceptible to chronic inflammation and fibrosis, and produces lower amounts of leptin than subcutaneous tissue.Excess visceral fat , but not subcutaneous fat, is involved in adiposity-related hypertension, mitochondrial dysfunction and oxidative stress.47(2022) Zammouri J, et al. Molecular and Cellular Bases of Lipodystrophy Syndromes. Front Endocrinol (Lausanne). 2022 Jan 3;12:803189. doi: 10.3389

48. AGENDACase PresentationLipodystrophy OverviewClassification of Lipodystrophic syndromesPathophysiology of LipodystrophyMechanism responsible for severe insulin resistanceFat Redistribution and Fat Metabolism Adipocytokines Inflammation: TNF-α / IL6Endoplasmic Reticulum and Mitochondrial Stress Insulin resistance & Acromegaloid feature Treatment of syndromes of lipodystrophies Lifestyle ModificationManagement of Insulin Resistance Management of DyslipidemiaManagement of Cosmetic Appearance Adipokines in Lipodystrophy48

49. Mechanism responsible for severe insulin resistanceThe mechanisms of insulin resistance in several syndromes associated with lipodystrophy are not fully understood.Fat Redistribution and Fat Metabolism Adipocytokines Inflammation: TNF-α / IL6Endoplasmic Reticulum and Mitochondrial Stress 49(2016) De Groot J, Larry Jameson MD PhD Leslie J, Endocrinology Adult & Pediatric 7th Edition P: 656,657

50. Mechanism responsible for severe insulin resistanceFat Redistribution and Fat Metabolism The lack of adipose tissue can result in inadequate storage of and therefore increased levels of free fatty acids (FFAs). Intracellular fatty acid accumulation can directly inhibit insulin-mediated glucose transport in skeletal muscle. Excess FFAs can lead to ectopic fat accumulation in the liver and muscle.The deposition of fat in the pancreas can also impair beta-cell response and further contribute to insulin resistance Lipodystrophic states that are associated with higher volume of visceral fat and abdominal fat are likely to display a higher degree of insulin resistance. 50(2016) De Groot J, Larry Jameson MD PhD Leslie J, Endocrinology Adult & Pediatric 7th Edition P: 656,657

51. Mechanism responsible for severe insulin resistanceAdipocytokines Leptin and adiponectin are two of the most abundant adipocytokines produced by adipocytes, and their levels decrease in the lipodystrophic states. Serum adiponectin levels correlate positively with insulin sensitivity and levels are upregulated by PPARγ agonists. Adiponectin acts by reducing hepatic gluconeogenesis (mainly via adiponectin receptor 2 and activation of AMPK phosphorylation) and increasing fatty acid oxidation in muscle (mainly via adiponectin receptor 1). Anti-inflammatory effects of adiponectin have also been proven. 51(2016) De Groot J, Larry Jameson MD PhD Leslie J, Endocrinology Adult & Pediatric 7th Edition P: 656,657

52. Mechanism responsible for severe insulin resistanceAdipocytokines Leptin and adiponectin are two of the most abundant adipocytokines produced by adipocytes, and their levels decrease in the lipodystrophic states. Aside from actions of leptin in the central nervous system (CNS), leptin may exert its insulin-sensitizing effects peripherally by decreasing gluconeogenesis in the liver and adipose tissue, by itslipolytic activity, and/or by increasing glucose utilizationin skeletal muscle. Leptin administration improves metabolic manifestations of HALS in humans in the short and long term. 52(2016) De Groot J, Larry Jameson MD PhD Leslie J, Endocrinology Adult & Pediatric 7th Edition P: 656,657

53. Mechanism responsible for severe insulin resistanceInflammation: Inflammatory adipocytokines, such as TNF-α, IL-6, IL-8, macrophage inflammatory protein (MIP)-1α and 1β, monocyte chemotactic protein-1 (MCP-1; also known as CCL-2), plasminogen activator inhibitor-1 (PAI-1), angiotensinogen, retinol binding protein-4 (RBP-4), and others have been implicated as the key regulators of insulin sensitivity. Accumulating evidence supports an association between inflammation and insulin resistance. TNF-α mediates insulin resistance via reduction of insulin receptor kinase activity, induction of lipolysis, and downregulation of GLUT-4. It may also induce apoptosis of adipocytes. IL-6: chronic elevation of IL-6 promotes hepatic insulin resistance and impedes differentiation of adipose tissue, whereas an acute elevation of IL-6 after exercise may promote improved glucose and lipid metabolism. 53(2016) De Groot J, Larry Jameson MD PhD Leslie J, Endocrinology Adult & Pediatric 7th Edition P: 656,657

54. Mechanism responsible for severe insulin resistanceEndoplasmic Reticulum and Mitochondrial Stress: Seipinopathy has recently been identified as an ER stress-associated disease.Mitochondrial dysfunction will lead to oxidative phosphorylation defects and reactive oxygen species (ROS) accumulation.Increased ROS levels are also associated with increased insulin resistance. Oxidative stress may also trigger beta-cell apoptosis and may contribute further to insulin resistance. 54(2016) De Groot J, Larry Jameson MD PhD Leslie J, Endocrinology Adult & Pediatric 7th Edition P: 656,657

55. AGENDACase PresentationLipodystrophy OverviewClassification of Lipodystrophic syndromesPathophysiology of LipodystrophyMechanism responsible for severe insulin resistanceFat Redistribution and Fat Metabolism Adipocytokines Inflammation: TNF-α / IL6Endoplasmic Reticulum and Mitochondrial Stress Insulin resistance & Acromegaloid feature Treatment of syndromes of lipodystrophies Lifestyle ModificationManagement of Insulin Resistance Management of DyslipidemiaManagement of Cosmetic Appearance Adipokines in Lipodystrophy55

56. Insulin resistance & Acromegaloid feature Rarely, patients exhibit soft tissue and skin changes usually associated with acromegaly but normal baseline and dynamic GH and IGF1 with no demonstrable pituitary or extra pituitary tumor, termed acromegaloid. Insulin resistance and defective IGF1 binding demonstrated in cells derived from some patients with acanthosis nigricans. ¹Insulin and IGF-I share a range of biological activities.Insulin and IGF-I both exhibit affinity for each other’s primary receptors. ²Activation intact mitogenic signaling pathways and stimulation pathological tissue growth induced by the extreme elevation of serum insulin occurring in compensation for the impaired metabolic signaling. ³561: (2020) Williams Textbook of Endocrinology, 14th edition P:2822: (2011) Sam AH, Tan T, Meeran K. Insulin-mediated "pseudoacromegaly". Hormones (Athens). 2011 Apr-Jun;10(2): 156-61. doi: 10.143103: (2019) Moradi L, Amiri F, Shahbazian H. Insulin resistance and pseudoacromegaly: A case report. Diabetes Metab Syndr. 2019 Mar-Apr;13(2):901-903. doi: 10.1016

57. Insulin resistance & Acromegaloid feature The human proinsulin polypeptide begins with the 30-amino-acid B chain domain, extends through a 35-amino-acid connecting segment & ends with the 21–amino-acid A chain domain.Mature IGF-1 and IGF-2 contain 70 and 67 amino acids & the regions homologous tothe B chain of insulin, the C peptide, the A chain and also a D extension peptide. Proinsulin has a longer C peptide region compared to IGF-1 or IGF-2. The A chain and B chain peptide regions are of similar length. The sequences in this region are 41% and 43% homologous with proinsulin. 57(2016) De Groot J, Larry Jameson MD PhD Leslie J, Endocrinology Adult & Pediatric 7th Edition P: 258,361

58. Insulin resistance & Acromegaloid feature 58(2020) Williams Textbook of Endocrinology, 14th edition P:1355

59. Insulin resistance & Acromegaloid feature The receptors are heterotetrameric glycoprotein composed of two ligand-binding subunits termed alpha subunits and two beta subunits. The IGF-1 receptor binds IGF-1 with a kd of M. IGF-2 binds with sixfold lower affinity, and insulin with a 200- to 300-fold lower affinity. α-subunit of both the IGF-1 and insulin receptors shows that there are two important differences, one in LR1 and one in CR1.The biological significance of hybrid receptor activation in tissues in whole animals has not been determined.  59(2016) De Groot J, Larry Jameson MD PhD Leslie J, Endocrinology Adult & Pediatric 7th Edition P: 362,363

60. Insulin resistance & Acromegaloid feature 60(2016) De Groot J, Larry Jameson MD PhD Leslie J, Endocrinology Adult & Pediatric 7th Edition P: 560

61. AGENDACase PresentationLipodystrophy OverviewClassification of Lipodystrophic syndromesPathophysiology of LipodystrophyMechanism responsible for severe insulin resistanceFat Redistribution and Fat Metabolism Adipocytokines Inflammation: TNF-α / IL6Endoplasmic Reticulum and Mitochondrial Stress Insulin resistance & Acromegaloid feature Treatment of syndromes of lipodystrophies Lifestyle ModificationManagement of Insulin Resistance Management of DyslipidemiaManagement of Cosmetic Appearance Adipokines in Lipodystrophy61

62. Treatment of syndromes of lipodystrophies Lifestyle modification, hypoglycemics, and lipid-lowering agents are generally required to treat metabolic disturbances associated with lipodystrophies. They commonly yield limited results. The development of new drugs targeted to specifically reverse insulin resistance is expected with great anticipation.Lifestyle ModificationManagement of Insulin Resistance Management of DyslipidemiaManagement of Cosmetic Appearance Adipokines in Lipodystrophy62(2016) De Groot J, Larry Jameson MD PhD Leslie J, Endocrinology Adult & Pediatric 7th Edition P: 657

63. Treatment of syndromes of lipodystrophies Lifestyle Modification The general clinical recommendations have been to follow the standard dietary advice regarding management of dyslipidemia, obesity, insulin resistance, and impaired glucosetolerance, with the goal of attaining ideal body weight. For patients with severe hypertriglyceridemia, an extremely low-fat diet (preferably <15% of daily caloric intake coming from fat) should be advised. For patients with fat atrophy, increased caloric intake may be necessary. Patients should also avoid alcohol consumption to prevent chylomicronemia and acute pancreatitis. Patients with lipodystrophy should also be advised on smoking cessation and optimal blood pressure control. 63(2016) De Groot J, Larry Jameson MD PhD Leslie J, Endocrinology Adult & Pediatric 7th Edition P: 657

64. Treatment of syndromes of lipodystrophies Management of Insulin ResistanceTraditional insulin sensitizers such as metformin and/or thiazolidinediones can be considered.MetforminMetformin, acting by inhibiting gluconeogenesis in the liver and increasing peripheral glucose utilization, has shown efficacy in improving insulin sensitivity in patientswith lipodystrophies.Other studies have cast doubt on the potential usefulness of metformin, however, by suggesting that metformin may lead to no changes in waist-to-hip ratio and may possibly cause further loss of limb fat. (These studies were done in HALS population)64(2016) De Groot J, Larry Jameson MD PhD Leslie J, Endocrinology Adult & Pediatric 7th Edition P: 657

65. Treatment of syndromes of lipodystrophies Management of Insulin Resistance Thiazolidinediones The thiazolidinediones (TZDs), acting by stimulating nuclear transcription factor PPARγ, have shown promise in treating patients with lipodystrophies. TZDs result in improved insulin sensitivity, but data on fat redistribution and lipid profiles have been variable and conflicting. Rosiglitazone may be associated with increased LDL and TG levels, a fact that makes it a less desirable drug to treat lipodystrophies.Pioglitazone, with its more favorable lipid profile, may have a more central place in the control of metabolic abnormalities. In one placebo-controlled randomized study, treatment with pioglitazone during a 1-year period increased serum adiponectin levels.65(2016) De Groot J, Larry Jameson MD PhD Leslie J, Endocrinology Adult & Pediatric 7th Edition P: 657

66. Treatment of syndromes of lipodystrophies Management of DyslipidemiaThe treatment of dyslipidemia in lipodystrophy should follow the same guidelines as in the general population, with the goal of total cholesterol level being less than 200 mg/dL, HDL 60 mg/dL or higher, LDL cholesterol less than 70 mg/dL, and triglyceride levels less than 150 mg/dL. Lipodystrophy-related dyslipidemia can be difficult to treat, and multiple agents may be necessary to lower lipids to target ranges. Statins: Among statins, pravastatin may also increase subcutaneous and limb fat. Fibrates Nicotinic Acid: Exacerbation of insulin resistance /Acipimox, a long-acting niacin analogue, may also improve triglycerides and improve insulin sensitivity 66(2016) De Groot J, Larry Jameson MD PhD Leslie J, Endocrinology Adult & Pediatric 7th Edition P: 658

67. Treatment of syndromes of lipodystrophies Management of Cosmetic AppearanceAutologous fat transplant and implantation of synthetic bulking agents have been used for the cosmetic correction of facial lipoatrophy and appear to be associated with improvements in quality of life. 67(2016) De Groot J, Larry Jameson MD PhD Leslie J, Endocrinology Adult & Pediatric 7th Edition P: 660

68. Treatment of syndromes of lipodystrophies Adipokines in LipodystrophyLeptinleptin acts mainly at the hypothalamus, particularly at the neurons containing pro-opiomelanocortin (POMC) and neuropeptide Y (NPY), to regulate food intake and fuel partitioning, may also work peripherally.Functional magnetic resonance imaging (fMRI) studies in humans confirm that leptin mediates its “adipostatic” effect through hypothalamic and other brain areas that are important in emotional and cognitive control.The administration of recombinant leptin (r-metHuLeptin or metreleptin) has shown amelioration of the metabolic abnormalities. 68(2016) De Groot J, Larry Jameson MD PhD Leslie J, Endocrinology Adult & Pediatric 7th Edition P: 660

69. Treatment of syndromes of lipodystrophies Adipokines in LipodystrophyLeptinSeveral small studies show that subcutaneous injection of Leptin (0.04 to 0.08 mg/kg/day) in patients with severe generalized lipodystrophy results in significant and sustained weight loss with decreased fat and lean body mass. Hypertriglyceridemia, usually refractory to traditional lipid-lowering agents, is commonly responsive to leptin treatment.The liver volume decreases with leptin treatment, most likely as a result of decreased intrahepatic lipid content.Potential side effects of metreleptin treatment, such as deterioration of renal function and possible occurrence of T-cell lymphomas, will require further investigation. 69(2016) De Groot J, Larry Jameson MD PhD Leslie J, Endocrinology Adult & Pediatric 7th Edition P: 660,661

70. Treatment of syndromes oflipodystrophies Adipokines in LipodystrophyLeptinSeveral small studies show that subcutaneous injection ofLeptin (0.04 to 0.08 mg/kg/day) in patients with severe generalized lipodystrophy results in significant and sustained weight loss with decreased fat and lean body mass. 70

71. Treatment of syndromes of lipodystrophies 71(2016) Meehan CA, et al. Metreleptin for injection to treat the complications of leptin deficiency in patients with congenital or acquired generalized lipodystrophy. Expert Rev Clin Pharmacol. 2016;9(1):59-68. doi: 10.1586

72. Treatment of syndromes of lipodystrophies Adipokines in LipodystrophyAdiponectin Adiponectin are attractive future targets for drug development based on the fact that adiponectin is decreased in lipodystrophic states and the evidence from mouse studies showing that adiponectin administration can improve insulin sensitivity, dyslipidemia, sustained weight loss without reducing food intake, and production of proinflammatory cytokines.Because of its complex molecular structure, synthetic adiponectin is not yet available for therapy in humans. 72(2016) De Groot J, Larry Jameson MD PhD Leslie J, Endocrinology Adult & Pediatric 7th Edition P: 661

73. Thanks for your attention73