Glucose Load Tolerance

in SMA type II

Thesis Defense
By: Beth Miller
Chair: Dr. Julie Metos RD, CD
Committee Members:
Rebecca Hurst Davis MS, RD, CSP, CD & Dr. Kristine Jordan
RD, CD
Background-SMA
O Severe neuromuscular disease
O Missing or abnormal SMN1 gene

O Rate of incidence 1 in 6,000-10,000 births

O Four classes: degree of motor function achieved and
age of onset

O Treatment by an interdisciplinary team

O Surgical procedures more frequent with proven benefits

Body Composition & Nutrition

O Nutrient intake, body composition, and bone mineral density in
SMA type I (Poruk et al. 2012)

O Nutrition-related studies in SMA type II limited
O Feeding difficulties contribute to low weight gain (Messina et al. 2008)
and type III (Chen et al. 2012)

O Despite being within normal ranges on BMI curve, high fat mass
indicated on DEXA (Sproule et al 2009)

O Patients with severely reduced lean body mass (<10% of body
weight), experience hypoglycemia during times of catabolic
stress (illness, fasting) (Orngreen et al 2003, Bruce & Jacobsen 1995)




Pancreatic & Glucose Abnormalities
O Glucose metabolism & pancreatic
developmental defects (Bowerman et al. 2012,
2014)
O SMA mice
O SMN depleted mice
O Autopsy from human SMA type I patients

O SMA mice experienced:
O fasting hyperglycemia, hyperglucagonemia,
and glucose intolerance after an intraperitoneal
glucose tolerance test (IPGTT)



Bowerman Cont.
O SMN depleted mice experienced:
O weight gain, hyperinsulinemia, and an increase in the
number of pancreatic -cells

O Challenged with a high fat diet:
O glucose levels during an IPGTT

O Pancreatic islets in mice and SMA type I human samples
exhibited:
O cells cells

O SMN protein when defective, leads to dysfunctional glucose
metabolism

Study Goals
O Determine whether preadolescents with SMA type II
display impaired glucose tolerance after glucose loading

O Assess body composition
O risk for metabolic disease
O Dietary intake/nutrition management

O Research directed at generating precise values:
O Blood chemistry values at dispersed time intervals
O Glucose intolerance during OGTT




Methods
O Clinical pilot study:
O 1. oral glucose tolerance test (OGTT)
O 2. fasting challenge

O Approved by the IRB of the University of Utah

O Study funding:
O Families of SMA
O National Center for Advancing Translational
Sciences of the NIH




Methods
O Target enrollment of 6
children (5-13 years) with
SMA II
O FSMA, current patients

O Inclusion criteria:
O Genetic diagnosis of
SMA 5q
O Clinical diagnosis of type
II SMA
O Ability to sit, but not walk

O Exclusion criteria:
O Acute illness
O Use of feeding tube
(>50%)
O Inability to swallow
safely
O Medical diagnosis of
diabetes
O Daily use of oral
hypoglycemic
agent/insulin therapy

Table 1.
Subject Characteristics and Body
Composition
Characteristic Measure
Male 4
Female 2
Caucasian 5
Black Hispanic 1
Age (years) 8.9 1.72
Height (cm) 131.8 13.8
Weight (kg) 35.6 8.3
BMI (kg/m) 20.5 2.9
Lean mass (kg) 10.44 6.93
Body fat (kg) 24.82 4.65
Body fat % 71.5713.09
Values are means SD; n = 6
Methods
Participants

O Preadolescents were
selected
O Dramatic growth and
development
O Surgical procedures
(scoliosis)

O Participants travelled from
out of state



Methods: Visit OGTT
O 2 pm---check into the University of Utahs Center for
Clinical and Translational Sciences (CCTS)

O 2:15-3:15---Consent/assent obtained

O 3:15---vitals collected

O 3:30---anthropometrics measured (wt/ht, TSF, MAC)

O Clinical assessment

O 4-5 pm---DEXA analysis
@ School of Medicine


OGTT cont.
O 5 pm---received standardized meal
O 8 pm---100 ml Pediasure snack

O Regular medication taken as needed
O Water or ice chips given ad lib

O Meal analysis:
O ESHA Food Processor
O ~400 calories eaten
O 15% protein, 52% carbohydrate, and 33% fat

O Overnight fast 8 hours



OGTT Cont.
O 6 am 1
st
void
O Urine assessed using KetoStix

O IV catheter placed
O NS drip with double stop cock
assembly

O Baseline labs:
O Hgb A1c, IGF-1, blood glucose, insulin, glucagon,
alanine, and cortisol
O 0.5 ml of blood (YSI)
O 6:45 am--- glucose drink (1.75 g glucose/kg) prepared

O 7 am----patient allowed 10-15 minutes to drink

O Blood samples collected @ intervals of 30 min
O @ 30, 60, 90, 120, 180 min
O Blood glucose, insulin, glucagon, alanine, and cortisol
O Analyzed by ARUP labs

O 180 min--- 0.5 ml blood (YSI )

O Urinary samples tested for ketones

O 10 am---Conclusion
O Meal of their choice delivered from the University of Utahs Hospital
cafeteria

Data Analysis
O Blood glucose and lab values compared to
established standards (ARUP Laboratories)

O Anthropometric data analyzed against:
O CDC standards
O NHANES data collected from 19992004

O Exploratory and descriptive in nature

Results: Blood Glucose

O 3 of the 6 pts. have glucose intolerance
O blood glucose (mg/dL)=155, 169, and 185

O Average value @ 146.33 27.62 mg/dL
O ADA (140 to 199 mg/dL)

O 4/6 pts. peaked at 30 min (1 at 60, 1 at 90)

O Pt. (E) experienced hypoglycemia @ 180 min (53 mg/dL)

O Hgb A1C normal for 5/6 pts.
O Pt (B) had 5.7%
0
50
100
150
200
250
0 30 60 90 120 180
M
g
/
d
L

Minutes
Figure 1: Glucose Ranges
A
B
C
D
E
F
Reference
Reference values (Knopf et al. 1977)
Results: Insulin
O Fasting values high for 5/6 pts.
O ARUP reference 3-19 (IU/mL)

O Insulin values increased over tenfold at the 30 minute
interval

O Continued to climb 4/6 pts. peaked @ 120 min
O (1 @ 60, 1 @ 90)

O All 6 pts. @ 2 hour mark had values from 244-929 IU/mL
O (normal = 22-79 IU/mL)




0
100
200
300
400
500
600
700
800
900
1000
0 30 60 90 120 180
I
n
s
u
l
i
n

I
U
/
m
L

Minutes
Figure 2. Insulin Ranges
A
B
C
D
E
F
Reference
Reference values (ARUP Laboratories )
Results-Insulin
O All 6 pts. have hyperinsulinemia.
O Range 1066-2641 (IU/mL

O Insulin sum of 300 (IU/mL) (Maruhama et al.
1981)

O 4/6 pts. have insulin resistance based on
HOMA-IR values



1069
1393
2641
1066
2120
2637
300
0
500
1000
1500
2000
2500
3000
T
o
t
a
l

i
n
s
u
l
i
n



Study Subjects
Hyperinsulinemia
A
B
C
D
E
F
Reference
Reference value (Maruhama et al. 1981)
Table 2. Insulin Resistance Characteristics
Study
Subjec
t
Fasting
Glucose
(mg/dL)
Fasting
Insulin
(IU/mL)
HOM
A IR
Referenc
e HOMA
IR
Insulin
Resistanc
e
Total
Insulin
(IU/mL)
Hyper-
insulin
emia
A 99 14 3.42 3.82 No 1069

Yes
B 103 31 7.89 2.67

Yes 1393

Yes
C 100 38 9.38 2.67

Yes 2641

Yes
D 85 20 3.78 2.67

Yes 1066

Yes
E 87 29 6.23 2.22

Yes 2120 Yes
F 91 22 4.94 5.22 No 2637 Yes
HOMA-IR=Fasting insulin x
Fasting glucose/405
prepubertal 8-9 years
Results: Body Composition
O 3/6 pts. have glucose intolerance
O body fat percentages of 56.7, 76.1, and 82.1%

O Pt A---low body fat (56.66%) and BMI of 15.60 kg/m
O impaired glucose tolerance @ 169 mg/dL

O 2 pts. (A, F) did not have insulin resistance
based on HOMA-IR pubertal values
O lowest body fat (56.66 and 53.52%)

O Pt (B) had the highest body fat @ 83.43%
O HgbA1c of 5.7%

Table 3. Body Composition and Glucose Metabolism

Study
Subject BMI
(kg/m)

BMI
%ile

BMI
Classificatio
n
Body
Fat %

HgbA1c
(%)
120 min
Glucose
(mg/dL)

HOMA
IR

A
15.60 16.4

Normal
56.66 5.3 169

3.42

B
18.87 90.9

Overweight
83.43 5.7 127

7.89

C
23.30 98.8

Obese
76.1 5.1 185

9.38

D
21.29 97.5

Obese
82.14 4.9 155

3.78

E
22.98 97.9

Obese
77.54 5.4 115

6.23

F
20.75 86.1

Overweight
53.52

4.9
127

4.94
Results: Other Labs
O 5/6 pts. alanine values were normal
O ARUP range of 150-570 mol/L

O Pt (C) had values >570 (mol/L)
O Peaked at baseline and lasted 2 hrs

O Cortisol values peaked at baseline 4/6 pts
O above reference (15 (g/dL))

O IGF-1 and glucagon values all WNL


Recap
O 3/6 pts. have glucose intolerance (OGTT)

O 4/6 have insulin resistance (HOMA-IR)

O All 6 pts. have hyperinsulinemia
O Total insulin 4-9 times (300 (IU/mL)

O No other documented OGTTs for SMA pts.


Discussion: Glucose Tolerance
O SMA disease severity based on SMN2 copy number

O Reduced SMN protein (regardless of SMA phenotype)
causes pancreatic/metabolic dysfunction (Bowerman et al.
2014)

O Slow progression of glucose abnormalities seen in our 6
pts.

O Screening protocol (OGTT) 1
st
step in better
understanding glucose metabolism/abnormalities
O Track changes

Discussion: Body Comp.
O All 6 pts. obese by NHANES reference standards (1999-2004)

O DEXA scans (8-12.99 yrs.):
O 95
th
%ile for boys: 41.1 - 43.3%
O girls: 43.3 - 44.4%

O Our pts. DEXA reveal:
O Average body fat @ 71.57% 13.09

O BMI based on CDC categories
O 83% overweight/obese
O 50% obese


Body Composition Cont.
O DEXA gold standard for accurate body
composition

O Despite being within normal ranges on
BMI curve, high fat mass indicated on
DEXA (Sproule et al 2009)
O BMI above 75
th
, 50
th
, and 3
rd
%iles
corresponded to a FMI >95
th
, >85
th
, and
>50
th
percentiles, for the SMA patients
Insulin Resistance
O All 6 pts. had reduced insulin sensitivity based on:
O total sum of insulin values and calculated HOMA-IR values

O Kurtolu et al. measured insulin and glucose metabolism in
200 obese children/adolescents (5 to 18 years)

O Based on OGTT values, HOMA-IR was applied and cut off
criteria for obese, children/adolescents was generated

O Rates of insulin resistance were based on pubertal status
O Prepubertal, 8-9 years, had a rate of insulin resistance of
37% (boys) and 27.8% (girls)
O Pubertal period: over 60% for both boys and girls

O 4/6 pts. met the criterion for insulin resistance based on their
HOMA-IR values corresponding to their age
Future Considerations
O Results provide evidence that as disease
progresses, glucose intolerance and insulin
resistance develops

O Dietary treatment necessary

O Awareness during illness/surgery
O IV dextrose and potential for hyperglycemia/rebound
hypoglycemia

O PT to preserve muscle mass/mobility




Strengths
O Inclusion criteria:
O Preadolescents with SMA type II
O No prior diagnosis of glucose intolerance/diabetes

O Taking anthropometric measurements (DEXA)
O Relationship between body composition and glucose
regulation

O Plasma measures to draw conclusions about:
O Metabolic abnormalities and glucose intolerance

Limitations
O No age-matched healthy peers
O Normal ranges well documented

O Minimal number of participants (n=6)
O Inferential statistical analysis not possible
O Benchmarks for:
O Dietary management

Conclusion
O Glucose metabolism abnormalities exist
for overweight/obese SMA pts.

O More research needed on a larger scale

O Nutrition therapy for the prevention of
metabolic disease
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