Diabetes: Across the Lifespan Friday, October 17, Obesity, Insulin Resistance and Type 2 Diabetes Cardiovascular Risks in Children.

Transcription

1 Diabetes: Across the Lifespan Friday, October 17, 2014 Obesity, Insulin Resistance and Type 2 Diabetes Cardiovascular Risks in Children. Don P. Wilson, M.D., FNLA Diplomate, Am Brd of Clinical Lipidology Pediatric Endocrinology Cook Children s Medical Center Fort Worth, Texas

2 Disclosures Osler Institute Speaker Aegerion Pharmaceuticals Advisory Board Merck Sharp & Dohme Research Funding Novo Nordisk Inc. Research Funding

3 Obesity,Insulin Resistance and Type 2 Diabetes Cardiovascular Risks in Children. Goal: Provide an overview of the pathophysiology, diagnostic evaluation, and treatment of children and adolescents with risk of premature CVD related to obesity, insulin resistance and T2DM. Objectives: Recognize the key genetic and acquired CVD risk factors. Understand the predisposing risk factors, including heredity, obesity, and lifestyle issues such as lack of physical activity and a poor diet. List the key interventions, treatment and desired outcomes.

4 Introduction Diabetes mellitus is one of the most serious and challenging endocrine conditions affecting children. The prevalence of both auto-immune (Type 1 Diabetes) and non auto-immune (Type 2 Diabetes) are increasing in children. Although effective, treatment of diabetes is costly, time consuming, and challenging for most children and their families.

5 Case Study Sarah You examine 16-year-old Sarah, a Hispanic girl with a recent history of unexplained weight loss. For the past 3 weeks she has noted increased thirst and urination.

6 Case Study Sarah Findings on physical examination include mild tachycardia and pallor. Her BMI is 32 kg/m 2, there is prominent acanthosis nigricans of her neck and axilla, and visceral adiposity.

7 Case Study Sarah Visceral adiposity Acanthosis nigricans

8 Based on your findings, which of the following tests would be the MOST informative? a. Blood glucose. b. Urinalysis. c. HgbA1c. d. Lipid profile. e. All of the above.

9 You find that Sarah s random blood glucose is 350 mg/dl and her urine is moderately positive for ketones. Given her presentation, which of the following is the MOST likely cause of her symptoms? a.acute urinary tract infection. b.diabetes mellitus. c.eating disorder. d.diabetes insipidus. e.none of the above.

10 In an individual with classic symptoms of diabetes, which of the following would be consistent with the ADA s criteria for diabetes? a. A fasting plasma glucose of 110 mg/dl. b. A 2-hour glucose level of 160 mg/dl during 75-g oral glucose tolerance test. c. A random plasma glucose of 210 mg/dl. d. HgbA1c of 6%. e. All of the above

11 DIABETES NORMAL PRE-DIABETES DIABETES HgbA1c <5.6% % >6.5% Fasting glucose < hour GTT < Random glucose 200* *Plus classic symptoms generally include polydipsia, polyuria and weight loss. The abrupt onset of nocturnal enuresis, daytime urinary incontinence and perineal canadiasis are also common.pre-diabetes = impaired fasting glucose or impaired glucose tolerance Reference: American Diabetes Association Clinical Guidelines 2014

12 Presentation of Diabetes Mellitus

13 DKA in Diabetes Mellitus About 30% of children with newly diagnosed T1DM present in DKA. Risk factors for having DKA at the initial presentation of type 1 diabetes include : Young age (<5 years of age;especially <2 years) Low socioeconomic status Delayed diagnosis Children living in countries with low prevalence of type 1 diabetes

14 Diabetic Ketoacidosis in T1DM and T2DM: Clinical and Biochemical Differences. Of 138 patients admitted for moderate-tosevere DKA. T1DM 70% T2DM 30% A greater proportion of the type 2 diabetes group was Latino American or African American (P<.001). Newton CA1, Raskin P. Arch Intern Med Sep 27;164(17):

15 Menses occurred at 11 yrs of age and was normal until 18 mos ago, at which time she experienced oligomenorrhea. No h/o of galactorrhea; moderate acne and hirsutism. Her free T4 is 1.2 ( ); TSH 7.2 ( ). A pelvic ultrasound is normal. Which of the following is the MOST likely cause of Sarah s oligomenorrhea? a.pregnancy. b.hypothyroidism. c.polycystic Ovarian Syndrome. d.hyperprolactinemia.

16 POLYCYSTIC OVARY SYNDROME Diagnosis by any 2 of the following: Oligomenorrhea or amenorrhea Elevated circulating androgens or clinical signs of androgen excess Polycystic ovaries by ultrasound [ultrasound not necessary in most cases]

17 POLYCYSTIC OVARY SYNDROME Laboratory evaluation: LH, FSH, prolactin, DHEAS, androstenedione, SHBG, free and total testosterone Treatment: (apart from weight loss) Oral contraceptives Metformin

18 Family History Both of Sarah s parents are obese. The father has dyslipidemia, hypertension and previously underwent bariatric surgery. The maternal GM and paternal GF both have T2DM.

19 The mother had gestational diabetes with all 3 of her pregnancies. Following her last pregnancy, mother s hyperglycemia persisted. During the 1 st year she was responsive to metformin monotherapy, but since that time has required insulin to maintain adequate control of her blood glucose.

20 Which of the following statements regarding the mother s gestational diabetes (GD) is TRUE? a. The mother s GD has no effect on the Sarah s risk of developing DM. b. The mother s GD will most likely get better with time, requiring only diet and exercise to maintain adequate glycemic control. c. The mother most likely has latent onset autoimmune DM and will always require insulin to maintain adequate glycemic control. d. The mother s GD places all of her children at increased risk of DM.

21 Diabetes Definitions Pre-gestational or Overt Diabetes include women diagnosed with type 1 or type 2 diabetes prior to becoming pregnant. Gestational Diabetes include glucose intolerance women first diagnosed while pregnant.

22 Types of DM in Pregnancy 5 to 10% of U. S. pregnancies are complicated by diabetes: T1DM women: 2% T2DM women: ~ 8% Gestational DM: ~ 90%

23 The Hyperglycemia and Adverse Pregnancy Outcome Study: Associations of GDM and Obesity with Pregnancy Outcomes Both maternal GDM and obesity are independently associated with adverse pregnancy outcomes. Their combination has a greater impact than either one alone. Diabetes Care April 2012 vol. 35 no

24 Does Type of Maternal Diabetes Matter? Several studies have found that the effects of exposure to diabetes in utero are similar for pregnancies complicated by T1DM, T2DM and gestational diabetes. Diabetes Care April 2012 vol. 35 no

25 The Hyperglycemia and Adverse Pregnancy Outcome Study: Associations of GDM and Obesity with Pregnancy Outcomes In the PIMA Indian Population, glucose levels where found to be associated with excess fetal growth and later risk of diabetes even among women with normal glucose tolerance tests. Diabetes Care April 2012 vol. 35 no

26 The Hyperglycemia and Adverse Pregnancy Outcome Study: Associations of GDM and Obesity with Pregnancy Outcomes Even small elevations in blood glucose levels in pregnancy are associated with increased maternal and fetal complications in pregnancy. Diabetes Care April 2012 vol. 35 no

27 The Hyperglycemia and Adverse Pregnancy Outcome Study: Associations of GDM and Obesity with Pregnancy Outcomes With each standard deviation increase in maternal blood glucose: Birth weight increased significantly. The risk of T2DM in the offspring increased by 30%. Diabetes Care April 2012 vol. 35 no

28 Study Conclusions Maternal T1DM, T2DM and gestational diabetes significantly increase the risk of obesity and diabetes in the offspring. Diabetes Care April 2012 vol. 35 no

29 Study Conclusions Furthermore, the excess risk of metabolic abnormalities in offspring, even in glucose tolerant mothers, suggests that exposure to hyperglycemia is a continuous risk factor. Mild hyperglycemia Pre-Diabetes Gestational Diabetes Type 1 or Type 2 Diabetes Diabetes Care April 2012 vol. 35 no

30 The parents want to know if it is better for Sarah to have T1DM or T2DM. Which of the following is the MOST appropriate answer to their question? a. Patients with T1DM and T2DM have the same rate of complications and long term outcome. b. Patients with T1DM have more complications than those with T2DM. c. Patients with T2DM have more complications than those with T1DM. d. The onset of either T1DM or T2DM < 18 yrs of age results in fewer long term complications than developing diabetes when you are an adult.

31 Long-term Complications and Mortality in Young-Onset Diabetes: T2DM Is More Hazardous and Lethal Than T1DM. Study Summary Observational study Compared outcomes in: 354 patients with T2DM who had onset between years of age 470 patients with T1DM who had a similar age of onset. Patients were followed for a median of more than 20 years in both groups. Constantino MI, Molyneaux L, Limacher-Gisler F, et al. Diabetes Care. 2013;36:

32 Long-term Complications and Mortality in Young-Onset Diabetes: T2DM Is More Hazardous and Lethal Than T1DM. Outcomes Studied: Retinopathy, neuropathy, renal function, ischemic heart disease, stroke, a composite of any macrovascular endpoint, and mortality. Controlled for age, sex, ethnicity, blood pressure, body mass index, A1c, cholesterol and triglyceride levels, albuminuria, smoking, and lipid-lowering therapy. Constantino MI, Molyneaux L, Limacher-Gisler F, et al. Diabetes Care. 2013;36:

33 Long-term Complications and Mortality in Young-Onset Diabetes: T2DM Is More Hazardous and Lethal Than T1DM. The 2 groups differed significantly, including age at onset, diabetes duration, and ethnicity. At the final clinical visit, less favorable CVD risk factors were found in the T2DM cohort, with significantly higher levels of serum triglyceride levels, lower HDL-C levels, and higher BP. Constantino MI, Molyneaux L, Limacher-Gisler F, et al. Diabetes Care. 2013;36:

34 Long-term Complications and Mortality in Young-Onset Diabetes: T2DM Is More Hazardous and Lethal Than T1DM. Despite a statistically shorter duration of diabetes and similar glycemic exposure, ischemic heart disease and stroke were much more common in the T2DM cohort, but there was no difference in retinopathy or renal function. Death was also more common among patients with T2DM, and it occurred after shorter disease duration. Constantino MI, Molyneaux L, Limacher-Gisler F, et al. Diabetes Care. 2013;36:

35 What is the mechanism of T1DM? Insulin Deficiency

36 What is the mechanism of T2DM? Insulin Resistance Insulin Deficiency Childhood Obesity

37 GLUT4 Shulman G I Physiology 2004;19: by American Physiological Society Skeletal Muscle

38 Increased Caloric Intake Defects in Adipocyte Fatty Acid Metabolism Increased Fat Delivery to the Liver Increased Fat Delivery to the Muscle Decreased Mitochondrial Fatty Acid Oxidation Shulman G I Physiology 2004;19: by American Physiological Society

39 Zucker rats were bred to be a genetic model for obesity research. Zucker rat (fa/fa) They are characteristically: Obese Have high levels of lipids and cholesterol And are resistant to insulin without being hyperglycemic Roger H. Unger. Longevity, lipotoxicity and leptin: the adipocyte defense against feasting and famine. Biochimie 87 (2005)

40 Zucker rat (fa/fa) Roger H. Unger. Longevity, lipotoxicity and leptin: the adipocyte defense against feasting and famine. Biochimie 87 (2005)

41 Which of the following statements is TRUE about the distinguishing characteristics of T1DM vs T2DM? a. Youth with T2DM are more likely to present with the classic symptoms of new-onset diabetes (i.e. polyuria, polydipsia, and weight loss) than those with T1DM. b. Diabetes-associated autoantibodies can be demonstrated at the time of diagnosis in the majority of those with T1DM. c. Type 2 diabetes is rarely associated with obesity, acanthosis nigricans, and features of the metabolic syndrome such as hypertension and dyslipidemia. d. Youth with T1DM are more are likely to be American Indian, Hispanic, and African-American ethnicities, compared with non-hispanic white youth.

42 Diabetes Related Antibodies Year (Total 34 mos) N 348 Ab - Null Total Ab Tested (%) % Positive GAD (97.9%) 73.3% ICA (95.9%) 37.7% Null = not tested

43 Youth with new-onset T1DM: Are more likely to present with the classic symptoms of new-onset diabetes (polyuria, polydipsia, severe hyperglycemia, ketonuria and DKA) at time of diagnosis. Have demonstrable diabetes-related autoantibodies at the time of diagnosis. Are more likely to be non-hispanic white youth than American Indian, Hispanic, and African-American ethnicities.

44 Youth with new-onset T1DM: Commonly have onset at 4-6 yrs of age and yrs of age. Have a normal or low BMI with a history of weight loss at presentation. Lack signs of insulin resistance, such as acanthosis nigricans, hypertension and polycystic ovarian syndrome (PCOS) in girls. Have a family history of T1DM in < 15 % of cases.

45 Youth with new-onset T2DM: Rarely have onset before puberty. Although more common in adulthood, onset may occur during adolescence. May present with DKA indistinguishable from those with T1DM. Is commonly associated with obesity, acanthosis nigricans, PCOS in girls, and features of the metabolic syndrome such as hypertension and dyslipidemia.

46 Youth with new-onset T2DM: Compared to T1DM are approximately 5 times more likely to have a 1 st degree family member with T2DM. Are more likely to be American Indian, Hispanic, and African-American ethnicities, compared with non-hispanic white youth.