Exercise and Endocrine Care

Eric Sherman MAJ, USAF, MC Pediatric Endocrine Fellow

Objectives
Discuss the maintenance of euglycemia Review some basics of exercise physiology Review exercise physiology in type 1 diabetes Review the literature on exercising safely with type 1 diabetes Review other endocrine disorders and any exercise recommendations

Fasting state
Reduced insulin secretion Increased levels of cortisol, GH, glucagon and epinephrine Glucose production enhanced Mobilization of fatty acids for energy

Sperling Pediatric Endocrinology

Fed state
Increased insulin secretion (w/in 20-30 min) and decreased glucagon secretion
Glycogen synthesis enhanced Enhanced glucose uptake in muscle Suppression of gluconeogenesis Lipid synthesis activated and lipolysis suppressed
Sperling Pediatric Endocrinology

Pierce Br. J. Sports Med (1999)

Exercise physiology
Decline in serum glucose

Decreased plasma insulin secretion

Increased counterregulatory hormones

Increased glucagon secretion

Muscular glucose production + Fatty acids mobilized from adipose tissue + Gluconeogenesis from lactate (liver) + GLUT4 stimulated transport of glucose into muscle

Euglycemia maintained

After exercise
Similar to fasting state Goal to rebuild skeletal muscle glycogen stores
Increased GLUT4 transport (insulin not initially required) Full replenishment of muscle stores requires insulin
Pierce Br. J. Sports Med (1999)

Counter regulatory hormones

Glucagon (alpha cells in pancreas)
Most efficient stimulator of gluconeogenesis Requires liver glycogen stores to acutely increase BG

Growth hormone (anterior pituitary)

Impaired glucose uptake Promotes lipolysis Increased hepatic glucose production
Sperling Pediatric Endocrinology

Counter regulatory hormones

Cortisol (adrenal cortex)
Enhances gluconeogenesis

Epinephrine (adrenal medulla)

More potent than norepi Inhibit insulin secretion Increase glucose secretion from liver and lactate from muscle

Norepinephrine (same as epi)

Sperling Pediatric Endocrinology

Quick Primer on Type 1 Diabetes

Incidence = ~20/100,000/year in US and Immune destruction of pancreatic beta cells Up to 40% of patients present after age 18 Treatment = insulin Prevention trials have all failed

Types of insulin
Short acting
Regular Aspart (Novolog) primary insulin in pumps Lispro (Humalog)

Intermediate acting
NPH

Long acting
Detemir Glargine (Lantus)

Insulin regimens
Traditional
NPH + regular (now Novolog/Humalog) in AM Novolog at dinner NPH at bedtime

Basal-bolus
Lantus once daily + Novolog at meals
Intensive treatment

CSII (insulin pump)

Diabetes and exercise

1. Exercise may decrease risk of diabetes complications 2. Hypoglycemia 3. Increased risk of DKA 4. Unmasking CAD

What is different in diabetes

Constant non-physiologic insulin supply Variable insulin absorption Suboptimal release of counter-regulatory hormones (especially during sleep) Increased skeletal muscle uptake following exercise Increased insulin sensitivity after exercise
McMahon JCEM (2007)

Exercise physiology in diabetes

Decline in serum glucose

Decreased plasma insulin secretion

Increased counterregulatory hormones

Increased glucagon secretion

Muscular glucose production + Fatty acids mobilized from adipose tissue + Gluconeogenesis from lactate (liver) + GLUT4 stimulated transport of glucose into muscle

Hypoglycemia

Hypoglycemia
Older data suggests that risk of hypoglycemia lasts up to 31 hours after exercise Macdonald Diabetes Care (2007) 2-4% of deaths in type 1 diabetes attributed to hypoglycemia Cryer Diabetes Care (2003) 2 episodes per week of severe hypoglycemia in well controlled diabetics Cryer Diabetes Care (2003) One episode of hypoglycemia blunts responses to subsequent hypoglycemia for several days Hopkins Diab
Res Clin Prac (2004)

And now for some real data

Biphasic Hypoglycemia
9 Australian adolescents exercised at ~ 55% VO2 peak (compared with 45 minutes of rest) moderate intensity Euglycemic clamp with constant insulin infusion and glucose adjusted to keep BG between 90-108 Primary endpoint: hypoglycemia as measured by increased GIR
McMahon JCEM (2007)

McMahon JCEM (2007)

McMahon JCEM (2007)

Early hypoglycemia
Lack of physiologic decrease in insulin secretion

Late hypoglycemia (MN 4AM)

Imbalance between glucose production and use Need to replete glycogen stores Blunted counter-regulatory responses during sleep

McMahon JCEM (2007)

Lack of hypoglycemia from 5P MN
Elevated counter-regulatory hormones may have increased fatty acid oxidation

Fatty Acids

Cortisol

Growth Hormone

DirecNet
A multi-center trial that studied the impact of exercise under a variety of conditions on 50 children with type 1 diabetes 75 minute exercise session at 4PM (55% VO2 max) 11/50 hypoglycemic (23%) BG < 60 26/50 had BG < 70 at some point Sharp rise in GH, but no change in cortisol or glucagon secretion
Diabetes Care (2006)

DirecNet
Initial BG < 120
86% hypoglycemic, 100% BG < 70

Initial BG 120-180
13% hypoglycemic, 44% BG < 70

Initial BG > 180

6% hypoglycemic, 28% BG < 70
Diabetes Care (2006)

Conclusions
Glucose production glucose utilization Counter regulatory hormones not doing their job, even in presence of hypoglycemia

Diabetes Care (2006)

DirecNet

10P 6A - mean BG 131 on exercise days and 154 on sedentary days Twice as many hypoglycemic events between 10P 6A on days with exercise compared to sedentary days
J Peds (2005)

How many carbs before exercise?

9 adult subjects on NPH and Novolog exercised for 60 minutes (50% VO2 max) with euglycemic clamp 3 hours post breakfast Given 0, 15 & 30 g of carbs prior to exercise Based on GIR and amount of pre-exercise carbs, a regression equation calculated 35 g of carbs prevents acute hypoglycemia 40 g of carbs prevents acute and late hypoglycemia
Dube Med & Sci in Sports & Exercise (2005)

Reduction in pre-meal insulin

8 adult males in randomized crossover trial
Exercised at 25, 50 & 75% of VO2 max for 30 and 60 minutes (90 minutes after eating) Injected 25, 50 & 100% of typical Humalog dose

100% of Humalog dose associated with significantly reduced BG compared with dose reduction (all groups)
Rabasa Lhoret Diabetes Care (2001)

Insulin pumps
Is suspending them an option?
50 patients aged 8-17 in random crossover trial (on and off pump during 75 minutes of exercise at 55% VO2 max)

DirecNet Diabetes Care (2006)

DirecNet Diabetes Care (2006)

Hypoglycemia

3 times more common in basal continued group Hyperglycemia 4.5 times more common in basal stopped group

Another pump study

10 patients exercised for 45 minutes (60% VO2 max) with pump on and pump off Wore CGMS for 24 hours after exercise No difference in hypoglycemic events during exercise (2 in each group) All 10 had 1-3 hypoglycemic events (BG 50-70) from 2.5 to 12 hours after exercise
Admon Pediatrics (2005)

Higher intensity exercise

7 adults
30 minutes of moderate exercise (40% VO2 max) 30 minutes of intermittent high intensity exercise (40% VO2 max + 4s sprints every 2 minutes)

IHE felt to mimic typical toddler activity and adolescent sports

Guelfi Diabetes Care (2005)

Guelfi Diabetes Care (2005)

Guelfi Diabetes Care (2005)

Why the difference?

Lactate
Inhibit glucose uptake within skeletal muscle Stimulate hepatic gluconeogenesis

Catecholamines
Inhibit insulin mediated glucose uptake Stimulate hepatic gluconeogenesis

GH
Inhibit insulin mediated glucose uptake
Guelfi Diabetes Care (2005)

A novel approach
7 adult males with type 1 diabetes in random crossover trial
Exercised for 20 minutes at 40% VO2 max +/a 10 s sprint at completion of exercise

Theorized that a short sprint would prevent hypoglycemia

Increase in lactate & catecholamines
Bussau Diabetes Care (2006)

Bussau Diabetes Care (2006)

Lactate

Fatty acids

Epinephrine

Norepinephrine

Growth hormone

Cortisol

Glucagon

Insulin

Bussau Diabetes Care (2006)

ADA and hypoglycemia

Avoid exercise if BG < 100 Have carbohydrates available during exercise

ADA Position Statement Diabetes Care (2004)

My recommendations
Avoid exercise if BG < 100 or > 300 Check ketones if BG > 250 and exercising Take 15 g of carbohydrates for every 30 minutes of exercise Check BG every 30-60 minutes during exercise and as needed Avoid using legs for injections p/t running (increased absorption) abdomen better

My recommendations
Check BG after exercise Disconnect pump during moderate to high intensity exercise, most sporting events and swimming Check BG prior to bedtime and eat snack with both carbohydrates and protein Check BG at 2A on intense exercise days

Insulin adjustment
No ADA recommendations No consensus statements Depends on timing & spontaneity of exercise Data suggests a 50% reduction in pre-meal insulin for planned exercise 25% decrease in evening Glargine if morning exercise planned
Pierce Br. J. Sports Med (1999)

Insulin adjustment
Post exercise
Consider decrease in insulin dose of 25-50%

Elite athletes
50-75% reduction in total daily insulin dose Hypoglycemia can occur up to 24-36 hours after competition (restoring muscle glycogen)
Pierce Br J Sports Med (1999)

Exercise & Hyperglycemia

Physiology
Insulin deficiency Hepatic glucose production continues without glucose utilization (exaggerated hyperglycemia) Increased lipolysis leads to FA and ketone production (exaggerated ketosis)
Zinker Clinics in Sports Med (1999)

ADA and hyperglycemia

Avoid exercise if BG > 250 and ketones present Use caution if BG > 300 and no ketones are present

ADA Position Statement Diabetes Care (2004)

Preparticipation evaluation
Vital signs Complete PE including monofilament evaluation A1C Yearly eye exam Microalbumin Fasting lipid panel TFTs Consider formal cardiac stress test

Exercise & cardiovascular dz

Stress test if
Age > 35 Age > 25 and
Type 2 diabetes for 10 years Type 1 diabetes for 15 years

Other CAD risk factors Retinopathy or nephropathy PVD Peripheral neuropathy

ADA Position Statement Diabetes Care (2004)

Exercise & Retinopathy

ADA Position Statement Diabetes Care (2004)

Exercise and Nephropathy

No specific recommendations ADA says high intensity/strenuous exercise should be avoided unless BP monitoring available Treatment may limit exercise capacity
ADA Position Statement Diabetes Care (2004)

Exercise and peripheral neuropathy

Loss of sensation in feet increases risk of ulcers Contraindicated Allowed
Treadmill Prolonged walking Jogging Stairmaster Swimming Biking Rowing Chair/arm exercises
ADA Position Statement Diabetes Care (2004)

Exercise & autonomic dysfunction

Difficult to diagnose
Resting HR > 100 Orthostasis Delayed gastric emptying

Cardiac stress test

Type 2 diabetes
Exercise benefits more clearly defined
HDL cholesterol, Total chol, LDL chol, TG BP insulin sensitivity weight loss ( insulin resistance) fatal cardiac events
Armen Clin Sports Med (2003)

Type 2 Diabetes
Decreased risk of hypoglycemia when taking oral agents Insulin therapy
Incidence of hypoglycemic events similar to type 1 diabetics when patients matched for duration of insulin therapy Hopkins Diab Res Clin Prac (2004)

Increased carbohydrate intake and BG monitoring prior to exercise recommended

Diabetes Care (2004)

Hemodynamic changes in thyroid disease

Hyperthyroidism
Peripheral vascular resistance
Circulation time Cardiac output

Hypothyroidism

Stroke volume
Cardiac index Arterial resistance Venous resistance Systolic/diastolic function Systolic blood pressure

Pulse pressure

widened

narrow
Kahaly Thyroid (2002)

Exercise and Hypothyroidism

No specific ATA recommendations Limited data about exercise in treated patients Subclinical hypothyroidism
No change in exercise parameters after 1 year of treatment (TSH 4.65 before treatment and 1.28 after treatment)
Caraccio JCEM (2005)

Exercise and Hyperthyroidism

No specific ATA recommendations Increased metabolic state with increased O2 consumption Increased risk of atrial fibrillation and rhabdomyolysis

Kahaly Thyroid (2002)

Exercise and Hyperthyroidism

What we recommend
Avoid exercise until T3 and T4 levels are normalized (may take several weeks) TSH may remain suppressed for several months (no impact on exercise tolerance)

Brief case report

45 yo white male with sarcoidosis Treated with prolonged steroid taper over 3 years (was on 2.5 mg/day at time of death) On Atenolol for 1 year for HTN Collapsed & died in June 1983 3.5 miles into marathon in Sheffield, England
Parsons Br J Sports Med (1984)

Brief case report

Missed Prednisone 2 days prior to race and on race day Autopsy revealed cortical atrophy and lipid depletion of adrenal glands (total weight 4 g)

Parsons Br J Sports Med (1984)

So what
LWPES and ESPE recommend that extra steroid dosing be considered when performing endurance sports

LWPES/ESPE Consensus Statement JCEM (2002)

CAH and High Intensity Exercise

Weise JCEM (2004)

Stress dose steroids??

Weise JCEM (2004)

CAH and Prolonged Exercise

Green-Golan JCEM (2007)

Review
Discussed the maintenance of euglycemia Reviewed some basics of exercise physiology Discussed exercise physiology in type 1 diabetes Reviewed the literature on exercising safely with type 1 diabetes Discussed other endocrine disorders and any exercise recommendations

Questions