Lipoatrophic Diabetes: What can zebras teach us about horses? Ranganath Muniyappa, MD, PhD Diabetes, Endocrinology, and Obesity Branch NIDDK, NIH

Size: px

Start display at page:

Download "Lipoatrophic Diabetes: What can zebras teach us about horses? Ranganath Muniyappa, MD, PhD Diabetes, Endocrinology, and Obesity Branch NIDDK, NIH"

Jeremy Leonard
5 years ago
Views:

1 Lipoatrophic Diabetes: What can zebras teach us about horses? Ranganath Muniyappa, MD, PhD Diabetes, Endocrinology, and Obesity Branch NIDDK, NIH

2 Objectives 1. Describe the clinical manifestations of abnormal reductions in adipose tissue mass 2. Recognize the pathogenic mechanisms mediating lipoatrophyassociated metabolic abnormalities 3. Discuss the therapeutic options to manage lipoatrophic diabetes

3 Lipodystrophy Syndromes Heterogeneous group of disorders Selective deficiency of adipose tissue

4 Classification of Lipodystrophies Etiology Genetic Acquired HIV/HAART associated Autoimmune Distribution of Body Fat Deficiency Partial Generalized

5 Classification of Lipodystrophies J Clin Endocrinol Metab Dec; 101(12):

6 Classification of Lipodystrophies Inheritance Pattern Subtype Lipodystrophy Phenotype Autosomal recessive CGL Near total absence of body fat, generalized muscularity, metabolic complications Genes Involved AGPAT2, BSCL2, CAV1, PTRF, PCYT1A, PPARγ FPLD Autoinflammatory Absence of fat in limbs, metabolic complications Variable absence of fat, variable metabolic complications CIDEC, LIPE, PCYT1A PSMB8 J Clin Endocrinol Metab Dec; 101(12):

7 Classification of Lipodystrophies Inheritance Pattern Subtype Lipodystrophy Phenotype Autosomal dominant FPLD Absence of fat from the limbs, metabolic complications SHORT syndrome Variable loss of body fat, metabolic complications Genes Involved LMNA, PPARG, AKT2, PL IN1 PIK3R1 Acquired AGL Near total absence of body fat, metabolic complications None APL Absence of fat in upper body with increased fat in lower body, mild or no metabolic complications None J Clin Endocrinol Metab Dec; 101(12):

8 Generalized vs. Partial lipodystrophy Muscular Appearance Acanthosis Nigricans Prominent Veins Prominent umbilicus Increased abdominal girth (hepatomegaly) Increased fat in head/neck /trunk

9 Major Comorbidities and Complications of Lipodystrophy Hyperphagia Complication Dyslipidemia (high triglycerides, low HDLcholesterol, acute pancreatitis, eruptive xanthomas) Insulin resistance/diabetes, acanthosis nigricans (and diabetes complications) Reproductive dysfunction (PCOS, oligomenorrhea, reduced fertility, hirsutism, preeclampsia, miscarriage, macrosomia) NAFLD (ranging from simple steatosis to cirrhosis) Renal dysfunction (proteinuria, MPGN, FSGS, diabetic nephropathy) Heart disease (hypertension, cardiomyopathy, arrhythmias, conduction abnormalities, CAD) Autoimmune disease Affected Subtypes AGL, CGL, ±FPLD AGL, CGL, FPLD AGL, CGL, FPLD AGL, CGL, FPLD AGL, CGL, FPLD, ±APL AGL, CGL, FPLD, APL AGL, CGL, FPLD AGL, APL J Clin Endocrinol Metab Dec; 101(12):

10 Pathophysiology of Lipodystrophy Excess calories cannot be stored in adipocytes Hyperphagia Ectopic lipid storage: - Muscle - Liver Starvation signal Diabetes Insulin resistance Low leptin Low fat mass Hypertriglyceridemia Non-Alcoholic Fatty Liver Disease 10

11 Diagnosis of Lipodystrophy Diagnosis of lipodystrophy is based on history, physical examination, body composition, and metabolic status. There are no defined serum leptin levels that establish or rule out the diagnosis of lipodystrophy. Confirmatory genetic testing is helpful in suspected familial lipodystrophies. Genetic testing should be considered in at-risk family members. Serum complement levels and autoantibodies may support diagnosis of acquired lipodystrophy syndromes. J Clin Endocrinol Metab Dec; 101(12):

12 Diagnosis of Lipodystrophy J Clin Endocrinol Metab Dec; 101(12):

13 Diagnosis of Lipodystrophy Core clinical characteristic for lipodystrophy Loss or absence of subcutaneous body fat in a partial or generalized fashion Core clinical characteristic for familial partial lipodystrophy:loss of subcutaneous body fat, typically occurring around or shortly after puberty, occurring in the extremities and/or gluteal region with sparing of fat loss or accumulation of excess fat in the face and neck or intraabdominal area Supportive clinical characteristics for lipodystrophy:presence of diabetes with evidence of severe insulin resistance Diabetes mellitus with requirement for high doses of insulin, eg, requiring 200 U/day, 2 U/kg/day, or currently taking U-500 insulin Ketosis-resistant diabetes Other evidence of severe insulin resistance Acanthosis nigricans PCOS or PCOS-like symptoms (hyperandrogenism, oligomenorrhea, and/or polycystic ovaries) Presence of hypertriglyceridemia Severe hypertriglyceridemia ( 500 mg/dl) Triglyceride levels that are non-responsive to therapy and/or modifications to diet ( 250 mg/dl) History of pancreatitis associated with hypertriglyceridemia Evidence of hepatic steatosis or steatohepatitis Hepatomegaly and/or elevated transaminases in the absence of a known cause of liver disease (eg, viral hepatitis) may be consistent with nonalcoholic fatty liver disease. Radiographic evidence of hepatic steatosis (e.g., on ultrasound or CT) Endocr Pract Jan-Feb; 19(1):

14 Diagnosis of Lipodystrophy Endocr Pract Jan-Feb; 19(1):

15 Diagnosis of Lipodystrophy Endocr Pract Jan-Feb; 19(1):

16 Treatment of Lipodystrophy Syndromes Diet Most patients should follow diets with balanced macronutrient composition. Energy-restricted diets improve metabolic abnormalities and may be appropriate in adults. Very-low-fat diets should be used in chylomicronemia-induced acute pancreatitis. A dietician should be consulted for specialized dietary needs, especially in infants and young children. Overfeeding should be avoided. Medium-chain triglyceride oil formulas can provide energy and reduce triglycerides in infants. J Clin Endocrinol Metab Dec; 101(12):

17 Treatment of Lipodystrophy Syndromes Currently, metreleptin (recombinant human methionyl leptin) is the only drug approved specifically for lipodystrophy In generalized lipodystrophy, metreleptin (with diet) is a first-line treatment for metabolic and endocrine abnormalities and may be considered for prevention of these comorbidities in children. Metreleptin may be considered for hypoleptinemic (leptin <4 ng/ml) patients with partial lipodystrophy and severe metabolic derangements (HbA1c >8% and/or triglycerides >500 mg/dl). J Clin Endocrinol Metab Dec; 101(12):

18 Treatment of Lipodystrophy Syndromes J Clin Endocrinol Metab Dec; 101(12):

19 Summary of Metreleptin Effects in Lipodystrophy Clinical Parameter Appetite and body weight Insulin resistance Diabetes Hypertriglyceridemia Steatohepatitis Reproduction Kidney disease Major Effects Decreased Decreased Decreased A1C Decreased insulin doses Decreased Improved Normalized menstrual cycles Increased fertility Decreased hyperfiltration Decreased protein excretion

20 Metreleptin in Generalized vs. Partial Lipodystrophy * *** Improvements in generalized lipodystrophy more consistent and of greater magnitude. In both generalized and partial lipodystrophy, greater benefits of metreleptin are seen in patients with more severe baseline abnormalities. 20

21 Dramatic Effects of Leptin in a Patient with Generalized Lipodystrophy 21 year old woman Poorly controlled diabetes with h/o DKA Severe hypertriglyceridemia Nephrotic range proteinuria 21

22 Before leptin 22 1 year on leptin

23 Leptin reverses nonalcoholic steatohepatitis in patients with severe lipodystrophy Hepatology, Volume41, Issue4, April 2005

24 Leptin reverses nonalcoholic steatohepatitis in patients with severe lipodystrophy Hepatology, Volume41, Issue4, April 2005

25 Treatment of Lipodystrophy Syndromes Diabetes Metformin is a first-line agent for diabetes and insulin resistance. Insulin is effective for hyperglycemia. In some patients, concentrated preparations and high-doses may be required. Thiazolidinediones may improve metabolic complications in partial lipodystrophy but should only be used with caution in generalized lipodystrophy. Dyslipidemia Statins should be used concomitantly with lifestyle modification (after consideration of age, reproductive status, and tolerance). Fibrates and/or long-chain omega-3 fatty acids should be used for triglycerides >500 mg/dl and may be considered for triglycerides >200 mg/dl. J Clin Endocrinol Metab Dec; 101(12):

26 Thank you

MYALEPT (metreleptin)

MYALEPT (metreleptin) Non-Discrimination Statement and Multi-Language Interpreter Services information are located at the end of this document. Coverage for services, procedures, medical devices and drugs