Presentation by Dr. Erin Keely (MD, FRCPC) at the Diabetes Perspectives... Ages and Stages Symposium (September 29, 2014)

1. Hormonal Changes and Diabetes- It can be a bumpy ride!!
Erin Keely
Chief, Division of Endocrinology and Metabolism, The Ottawa Hospital
ekeely@toh.on.ca

2. Objectives
•
Outline how hormonal changes affect insulin resistance and blood glucose levels
•
Discuss how pregnancy impacts glucose control in women with diabetes and predicts risk of future diabetes in those with gestational diabetes
•
Define androgen deficiency and how to screen for it in men with erectile dysfunction
•
Describe impact of menopause and hormone replacement therapy for women with diabetes

3. Gender differences in diagnosis of diabetes
•
Women more likely to be diagnosed with postprandial glucose levels vs fasting levels
•
Might miss women if only do a fasting glucose
•Reasons not clear

4. Impact of Pregnancy on Glucose Control

5. What’s the difference between type 1 and 2 for pregnancy?
•
Comorbidities
–
type 1 – autoimmune - thyroid disorders, nephropathy
–
type 2 - hypertension, hyperlipidemia, obesity, PCOD
•
Treatment
–
oral agents vs. insulin
–
Type 2 often on statins, multiple antiHTN
•
Pre-pregnancy care
–
type 2 may be considered less severe
–
older, often recent immigrants
–
May have low expectations of fertility
–
Health care providers
–
Self management

6. Why is preconception care important?
•
Reduction of congenital anomalies
•Reduction of spontaneous losses
•Optimization of complications and associated conditions
–And encourage effective contraception until obtained
•Modify therapies if appropriate
–Change to safest medications
–Avoidance of disruption of effective glycemic and blood pressure control

7. Glucose is a teratogen

8. Change to insulin prepregnancy unless using metformin for ovulation induction
But if conceive on oral agents do not stop medications until insulin is started
HYPERGLYCEMIA IS WORSE THAN THE MEDICATIONS

9. Target: A1c < 0.07
HgbA1c and Congenital Anomalies

10. +ve pregnancy test
MD appt

11. First trimester changes
•
Fasting glucose falls
–
first change
–
nadir of 3.5 mmol/l in 1st trimester
•Increased hypoglycemia unawareness
–decreased counter regulatory response
•Rapid acting insulin takes longer to work
–Need to take in advance of meal

12. 01020304050600510152025303540
Weeks of Pregnancy
Prolactin
Cortisol
HPL
Progesterone
HCG
hGH--V
Changes in Hormones of Pregnancy During Gestation

13. Insulin requirements increase 2-3 fold during 2nd and 3rd trimester
•
Is a GOOD thing
•
Sign of a healthy placenta
•
If requirements start dropping suggests placental insufficiency
–
Small for gestational age, fetal death, pre-eclampsia, placental abruption
Padmanabhan et al, Diabetes Care Oct 2014

14. Higher risk of DKA in pregnancy
•
Accelerated starvation state
–
Faster to make ketones
•Increased GFR
–Will spill glucose at lower serum glucose levels
–Blood glucose will not be as high when getting ketotic
–Need high index of suspicion even if glucose only 14-16 mmol/l
•Less buffering ability
–Compensated respiratory alkalosis
–Renal excretion of HCO3
–worse acidosis
•Insulin resistance – need higher doses of insulin to reverse
•Risk to fetus – up to 50% mortality

15. Peripartum
•
Discontinue s.c. insulin when in active labour or if having elective c-section
•use IV insulin peripartum
•restart s.c. insulin when eating
–2/3 of prepregnancy dose

16. Interpregnancy care
•
Personal experience of a poor pregnancy outcome does not encourage and may even discourage high-risk women from attending preconception care
•Need to provide postpartum support and ongoing care
•what would help you be bettered prepared for your next pregnancy?
•what would make this difficult?

17. Gestational Diabetes
•
Carbohydrate intolerance with onset or first recognition in pregnancy –NOT IN 2013
•
2-4% of pregnancies- NOT IN 2013
•Same risk factors as type 2 diabetes

18. Reasons to look for GDM

19. Diagnostic criteria for GDM

20. HAPO: Incidence of Adverse Outcomes for Glucose Categories (OR 1.75 or 2.0 )
Metzger BE, et al. HAPO. NEJM 2008;358(19):1991-2002.

21. 2013 GDM Diagnosis: Two Approaches
2013

22. To diagnose overt diabetes in first trimester
IADSPG Consensus Panel, Diab Care 2010

23. Gestational Diabetes Predicts Type 2 Diabetes
The Fourth Trimester

24. Rates of Postpartum Type 2 Diabetes in Mothers with GDM
•
Women with GDM have 20% risk of type 2 diabetes within 9 years compared to 2% in women without GDM
Feig, CMAJ July 29, 2008

25. Risk of postpartum GDM predicted by rate of abnormal glucose tolerance in pregnancy
Kramer, Diab Care online Sept 2014

26. Risk perception
N=89, 9-11 yr postpartum, Ottawa
–32% no idea/no different
–33% increased a little
–35% increased a lot
–15% had previously undiagnosed diabetes
–48% had abnormal GTT
Malcolm, Obstetric Medicine 2009;2:107-10

27. •rate of postpartum screening increased from 14% to 60% if a reminder was sent to the patient, her family physician or both

28. Breastfeeding associated with better maternal and offspring outcomes
•
May reduce offspring obesity and risk of type 2 diabetes
•Lactation may attenuate unfavourable metabolic risk factors, promote pp weight loss
–Gunderson Obstet Gynecol 2007
Need to target this group for breastfeeding support

29. Exclusive Breastfeeding on d/c
T1 Diabetes
Type 2 Diabetes
GDM
Others
2007- 2008
40%
(83%)
46%
(88%)
57%
(90%)
66%
(89%)
2008- 2009
36%
(87%)
51%
(86%)
49%
(91%)
62%
(89%)
Source: BORN Ontario (Niday Perinatal Database)

30. Postpartum GDM Management Checklist
1.
Encourage Breastfeeding
2.
75g OGTT between 6 weeks - 6 months postpartum to detect prediabetes or diabetes
3.
Discuss increased long-term risk of diabetes – Importance of returning to pre-pregnancy weight

34. Case
•
A 53 year old man with newly diagnosed diabetes is referred for education and self management. He has not been started on any medications yet. He has noticed some erectile dysfunction
•
He has been reading online and asks about taking testosterone supplements to improve his glucose levels
•
You advise him….

35. Causes of erectile dysfunction
•
Psychological
•Organic
–Vascular
•Strong predictor of other cardiovascular disease
–Neurological
–Hormonal
•All men with ED should have testosterone (LH, FSH, Prolactin) done

36. What does testosterone do?

38. Control of Androgen Production
•
Primary hypogonadism
–
Testicular failure
–
High LH, FSH
•
Secondary hypogonadism
–
Hypothalamic or pituitary cause
–
Low FSH and LH

39. Late onset androgen deficiency
•
Gradual decline in androgen levels in aging
•Biochemical test vs. symptom complex

40. How do we diagnose androgen deficiency?
•
What is normal?
–
Can 30% of men with diabetes really have low testosterone?
•
Which test to use
–
Total testosterone or free testosterone
•
Total testosterone
–
Normal > 12 nmol/l
–
Abnormal < 8 nmol/l

41. Association of Androgen Deficiency and Type 2 Diabetes
•
Testosterone deficiency more likely in men with type 2 diabetes
•
Diabetes/metabolic syndrome more likely in men with testosterone deficiency

44. Low testosterone levels associated with lower survival rates
Traish, Am J Med 2011

45. So what about testosterone replacement in men with diabetes?
•
Goals
–
Lipid profile
–
Decreased atherogenesis
–
Improved bone health
–
Improved overall health
–
Increased survival
•
Evidence
–
Decreases HDL
–
Improved mortality
–
UNLESS known heart disease (men undergoing angiography had 29% higher all cause mortality if put on androgens)
–
No studies on bone health and diabetes

46. Improvement in glycemic control in new diagnosis
•
32 men with new diabetes randomized to diet and exercise vs. diet/exercise and testosterone
•
Improved glycemic control with no medications
•
Improved lipid profile
With testosterone replacement
Heufelder J Androl 2009

47. Testosterone replacement
•
Needs to be followed carefully
–
Testosterone levels
–
Hematocrit
–
PSA
–
Clinical response
•
Relief of symptoms
•
Bone health
•
Metabolic syndrome

48. Goals of treatment
•
Relief of symptoms
•
Bone health
•
?improvement in metabolic syndrome

49. Case
•
A 53 year old man with newly diagnosed diabetes is referred for education and self management. He has not been started on any medications yet. He has noticed some erectile dysfunction
•
He has been reading online and asks about taking testosterone supplements to improve his glucose levels
•
You advise him….

50. Menopause and Diabetes

51. Definition of menopause
•
Perimenopause
–
Irregular menses – cycle length variation of more than 7 days from usual
•
Menopause
–
12 months of amenorrhea

52. Symptoms of menopause
•
Vasomotor
•
Vaginal dryness
•
Urinary incontinence
•
Sleep disturbance

53. Important menopausal issues for women with diabetes
•
Women with Type 1 diabetes may go through menopause earlier
–
Conflicting data – one study suggested 6 fewer fertile years in type 1 diabetes
–
Autoimmune premature ovarian failure in women with type 1
•
Women with diabetes may have difficulty distinguishing hot flashes from hypoglycemia
•
Increased abdominal fat, decreased lean body mass associated with menopause
–
Increased insulin resistance
•
Women with type 2 diabetes at more risk of endometrial and maybe breast cancer
•
Osteoporosis
–
Lower BMD more common in women with type 1 diabetes compared to women without diabetes
–
Higher BMD in women with type 2 diabetes (lower if on glitazones)
–
Despite BMD fractures more common- ?more falls, change in bone structure, vascular changes
•
increased risk of foot fractures with exercise

54. Effects of HRT in women with diabetes
1.
Impact on glucose control
–
Reduced insulin resistance
•
Lower fasting glucose levels compared to no HRT in women with diabetes
•
30% reduction in incidence of diabetes in women taking HRT vs. no HRT

55. 2. Impact on CV risk
-avoid in all women with known CV disease
3. Risk of breast cancer
4. Benefits for osteoporosis
5. Severity of vasomotor symptoms
AACE guidelines 2011

56. Summary
•
Any change in sex hormone levels may impact risk of having diabetes and change glucose levels in individuals with diabetes
•
In general, hormone replacement does not worsen glucose control or lipid levels. Biggest risk is in individuals known to have CV disease
•
Men with diabetes more likely to be hypogonadal but full understanding of risks/benefits and best approach to replacing androgens in not known
•
Women with diabetes have unique issues that need to be identified during menopause
–
Risk/benefits of hormone replacement is an individual decision between the patient and her