![Page 1: FETAL HYPERGLYCEMIA AND HYPERINSULINEMIA …...fetal hyperglycemia and hyperinsulinemia program tissue-specific postnatal insulin resistance. disclosure](https://reader030.vdocuments.us/reader030/viewer/2022040201/5e468cdb0a3b3c056a46e3e3/html5/thumbnails/1.jpg)
Kok Lim Kua, MDNeonatal-Perinatal Medicine Fellow
Stead Family Department of PediatricsUniversity of Iowa Children’s Hospital
FETAL HYPERGLYCEMIA AND HYPERINSULINEMIA PROGRAM TISSUE-
SPECIFIC POSTNATAL INSULIN RESISTANCE
![Page 2: FETAL HYPERGLYCEMIA AND HYPERINSULINEMIA …...fetal hyperglycemia and hyperinsulinemia program tissue-specific postnatal insulin resistance. disclosure](https://reader030.vdocuments.us/reader030/viewer/2022040201/5e468cdb0a3b3c056a46e3e3/html5/thumbnails/2.jpg)
Disclosure
• I have no relevant financial relationships with the manufacturer(s) of any commercial product(s) and/or provider(s) of commercial services discussed in this CME activity
• I DO NOT intend to discuss an unapproved/investigative use of a commercial product/device in my presentation
![Page 3: FETAL HYPERGLYCEMIA AND HYPERINSULINEMIA …...fetal hyperglycemia and hyperinsulinemia program tissue-specific postnatal insulin resistance. disclosure](https://reader030.vdocuments.us/reader030/viewer/2022040201/5e468cdb0a3b3c056a46e3e3/html5/thumbnails/3.jpg)
INCREASED RISK OF INSULIN RESISTANCE STATES IN OFFSPRING
• Similar findings in rodent experiments.
Maternal Condition
Offspring Outcome Risk Reference
Diabetes T2DM OR - 3.7 Dabelea 2000Gest IGTT T2DM Risk 51% vs 8% Franks 2006GDM/T1DM Prediabetes/T2DM OR 7.76 Clausen 2008DM/Obesity T2DM OR 3.9 Dabelea 2008GDM Obese/MetSyn OR obese 2/MetSyn4 Clausen 2009GDM Obese OR 1.61 Baptiste-Roberts 2012GDM Obese OR 1.81 Nehring 2013
![Page 4: FETAL HYPERGLYCEMIA AND HYPERINSULINEMIA …...fetal hyperglycemia and hyperinsulinemia program tissue-specific postnatal insulin resistance. disclosure](https://reader030.vdocuments.us/reader030/viewer/2022040201/5e468cdb0a3b3c056a46e3e3/html5/thumbnails/4.jpg)
MATERNAL-NEONATAL DIABETES TRANSMISSION
Adapted from NIH NIDDK 2011
![Page 5: FETAL HYPERGLYCEMIA AND HYPERINSULINEMIA …...fetal hyperglycemia and hyperinsulinemia program tissue-specific postnatal insulin resistance. disclosure](https://reader030.vdocuments.us/reader030/viewer/2022040201/5e468cdb0a3b3c056a46e3e3/html5/thumbnails/5.jpg)
FETAL ORIGINS OF DIABETESMaternal Diabetes
Offspring Insulin Resistance Later in Life
![Page 6: FETAL HYPERGLYCEMIA AND HYPERINSULINEMIA …...fetal hyperglycemia and hyperinsulinemia program tissue-specific postnatal insulin resistance. disclosure](https://reader030.vdocuments.us/reader030/viewer/2022040201/5e468cdb0a3b3c056a46e3e3/html5/thumbnails/6.jpg)
FETAL ORIGINS OF DIABETESMaternal Diabetes
- Abnormal Fuel- Hyperglycemia- Ketone- Fatty Acids- Amino Acids
- Placental Insufficiency- Reactive Oxygen Species
Acute Disruption of Fetal Insulin Signaling
Offspring Insulin Resistance Later in Life
![Page 7: FETAL HYPERGLYCEMIA AND HYPERINSULINEMIA …...fetal hyperglycemia and hyperinsulinemia program tissue-specific postnatal insulin resistance. disclosure](https://reader030.vdocuments.us/reader030/viewer/2022040201/5e468cdb0a3b3c056a46e3e3/html5/thumbnails/7.jpg)
FETAL ORIGINS OF DIABETESMaternal Diabetes
- Abnormal Fuel- Hyperglycemia- Ketone- Fatty Acids- Amino Acids
- Placental Insufficiency- Reactive Oxygen Species
Acute Disruption of Fetal Insulin Signaling
Offspring Insulin Resistance Later in Life
Fetal Hyperglycemia
Fetal Hyperinsulinemia
![Page 8: FETAL HYPERGLYCEMIA AND HYPERINSULINEMIA …...fetal hyperglycemia and hyperinsulinemia program tissue-specific postnatal insulin resistance. disclosure](https://reader030.vdocuments.us/reader030/viewer/2022040201/5e468cdb0a3b3c056a46e3e3/html5/thumbnails/8.jpg)
HYPOTHESIS
Fetal exposure to hyperglycemia acutely disrupts fetal insulin signaling and induces
insulin resistance later in life
![Page 9: FETAL HYPERGLYCEMIA AND HYPERINSULINEMIA …...fetal hyperglycemia and hyperinsulinemia program tissue-specific postnatal insulin resistance. disclosure](https://reader030.vdocuments.us/reader030/viewer/2022040201/5e468cdb0a3b3c056a46e3e3/html5/thumbnails/9.jpg)
LOCALIZED FETOMATERNAL HYPERGLYCEMIA MODEL
• Catheter placement with tip past the uterine artery take off.
Glucose4 mg/min
Yao 2010, Gordon 2015
Gestation 48h Glucose infusion
Surgery
Acute Effect
Late Effect
![Page 10: FETAL HYPERGLYCEMIA AND HYPERINSULINEMIA …...fetal hyperglycemia and hyperinsulinemia program tissue-specific postnatal insulin resistance. disclosure](https://reader030.vdocuments.us/reader030/viewer/2022040201/5e468cdb0a3b3c056a46e3e3/html5/thumbnails/10.jpg)
OUTCOME: INSULIN SENSITIVITY
Insulin Receptor
AKT p-AKT
Insulin
![Page 11: FETAL HYPERGLYCEMIA AND HYPERINSULINEMIA …...fetal hyperglycemia and hyperinsulinemia program tissue-specific postnatal insulin resistance. disclosure](https://reader030.vdocuments.us/reader030/viewer/2022040201/5e468cdb0a3b3c056a46e3e3/html5/thumbnails/11.jpg)
FETAL HYPERGLYCEMIA REDUCES FETAL INSULIN SENSITIVITY
Gestation 48h Glucose infusion
Experimental Timeline Surgery ±Insulin
• N = 23 pups/group, 10 moms, p<0.05
![Page 12: FETAL HYPERGLYCEMIA AND HYPERINSULINEMIA …...fetal hyperglycemia and hyperinsulinemia program tissue-specific postnatal insulin resistance. disclosure](https://reader030.vdocuments.us/reader030/viewer/2022040201/5e468cdb0a3b3c056a46e3e3/html5/thumbnails/12.jpg)
FETAL HYPERGLYCEMIA REDUCES FETAL INSULIN SENSITIVITY
Gestation 48h Glucose infusion
Experimental Timeline Surgery ±Insulin
• N = 4 pups/group, 2 mom
• N = 23 pups/group, 10 moms, p<0.05
![Page 13: FETAL HYPERGLYCEMIA AND HYPERINSULINEMIA …...fetal hyperglycemia and hyperinsulinemia program tissue-specific postnatal insulin resistance. disclosure](https://reader030.vdocuments.us/reader030/viewer/2022040201/5e468cdb0a3b3c056a46e3e3/html5/thumbnails/13.jpg)
FETAL HYPERGLYCEMIA DECREASES OFFSPRING INSULIN SIGNALING
Gestation 48 Glucose infusion
Experimental Timeline Surgery C section
Postnatal Life
Cross Foster Evaluation
21dPND 0
• N = 9 vs 19 pups from 6-8 moms
• No difference in liver tissue
Control HG
![Page 14: FETAL HYPERGLYCEMIA AND HYPERINSULINEMIA …...fetal hyperglycemia and hyperinsulinemia program tissue-specific postnatal insulin resistance. disclosure](https://reader030.vdocuments.us/reader030/viewer/2022040201/5e468cdb0a3b3c056a46e3e3/html5/thumbnails/14.jpg)
FETAL ORIGINS OF DIABETESMaternal Diabetes
- Abnormal Fuel- Hyperglycemia- Ketone- Fatty Acids- Amino Acids
- Placental Insufficiency- Reactive Oxygen Species
Acute Disruption of Fetal Insulin Signaling
Offspring Insulin Resistance Later in Life
Fetal Hyperglycemia
Fetal Hyperinsulinemia
![Page 15: FETAL HYPERGLYCEMIA AND HYPERINSULINEMIA …...fetal hyperglycemia and hyperinsulinemia program tissue-specific postnatal insulin resistance. disclosure](https://reader030.vdocuments.us/reader030/viewer/2022040201/5e468cdb0a3b3c056a46e3e3/html5/thumbnails/15.jpg)
HYPOTHESIS 2
Fetal hyperinsulinemia during late gestation leads to insulin resistance at postnatal day 21
![Page 16: FETAL HYPERGLYCEMIA AND HYPERINSULINEMIA …...fetal hyperglycemia and hyperinsulinemia program tissue-specific postnatal insulin resistance. disclosure](https://reader030.vdocuments.us/reader030/viewer/2022040201/5e468cdb0a3b3c056a46e3e3/html5/thumbnails/16.jpg)
FETAL HYPERINSULINEMIA MODEL
• Trans-utero injection of long acting insulin (Levemir) vs saline
Nijagal A, 2011
Gestation 48 hourInjection (Long acting Insulin)
Fetal Evaluation
Offspring Evaluation
![Page 17: FETAL HYPERGLYCEMIA AND HYPERINSULINEMIA …...fetal hyperglycemia and hyperinsulinemia program tissue-specific postnatal insulin resistance. disclosure](https://reader030.vdocuments.us/reader030/viewer/2022040201/5e468cdb0a3b3c056a46e3e3/html5/thumbnails/17.jpg)
FETAL HYPERINSULINEMIA SUPPRESSED INSULIN SIGNALING ACUTELY
Gestation 48 hour
Experimental Timeline EvaluationLong acting insulin
![Page 18: FETAL HYPERGLYCEMIA AND HYPERINSULINEMIA …...fetal hyperglycemia and hyperinsulinemia program tissue-specific postnatal insulin resistance. disclosure](https://reader030.vdocuments.us/reader030/viewer/2022040201/5e468cdb0a3b3c056a46e3e3/html5/thumbnails/18.jpg)
DECREASED LIVER INSULIN STIMULATED AKT-SIGNALING AT PND 21
Gestation 48 hour
Experimental Timeline Natural Birth
Postnatal Life
Evaluation
21d0
Long acting insulin
![Page 19: FETAL HYPERGLYCEMIA AND HYPERINSULINEMIA …...fetal hyperglycemia and hyperinsulinemia program tissue-specific postnatal insulin resistance. disclosure](https://reader030.vdocuments.us/reader030/viewer/2022040201/5e468cdb0a3b3c056a46e3e3/html5/thumbnails/19.jpg)
CONCLUSION
• Fetal hyperglycemia and fetal hyperinsulinemia programs tissue specific insulin resistance– Acute/Fetal
• Hyperglycemia – Insulin resistance in muscle• Hyperinsulinemia –Insulin resistance in muscle
– Postnatal Day 21• Hyperglycemia – Insulin resistance in muscle• Hyperinsulinemia – Insulin resistance in liver
![Page 20: FETAL HYPERGLYCEMIA AND HYPERINSULINEMIA …...fetal hyperglycemia and hyperinsulinemia program tissue-specific postnatal insulin resistance. disclosure](https://reader030.vdocuments.us/reader030/viewer/2022040201/5e468cdb0a3b3c056a46e3e3/html5/thumbnails/20.jpg)
ACKNOWLEDGEMENT• Norris Lab
– Dr Andrew Norris– Shanming Hu– Dr Jianrong Yao– Dr Areej Younes
• University of Iowa Division of Neonatology
• Funding• FOEDRC• CMN grant• Marshall Klaus Award
![Page 21: FETAL HYPERGLYCEMIA AND HYPERINSULINEMIA …...fetal hyperglycemia and hyperinsulinemia program tissue-specific postnatal insulin resistance. disclosure](https://reader030.vdocuments.us/reader030/viewer/2022040201/5e468cdb0a3b3c056a46e3e3/html5/thumbnails/21.jpg)
Supplemental Data
![Page 22: FETAL HYPERGLYCEMIA AND HYPERINSULINEMIA …...fetal hyperglycemia and hyperinsulinemia program tissue-specific postnatal insulin resistance. disclosure](https://reader030.vdocuments.us/reader030/viewer/2022040201/5e468cdb0a3b3c056a46e3e3/html5/thumbnails/22.jpg)
STUDY OUTCOME: INSULIN SIGNALING AS MEASURED BY AKT PHOSPHORYLATION
![Page 23: FETAL HYPERGLYCEMIA AND HYPERINSULINEMIA …...fetal hyperglycemia and hyperinsulinemia program tissue-specific postnatal insulin resistance. disclosure](https://reader030.vdocuments.us/reader030/viewer/2022040201/5e468cdb0a3b3c056a46e3e3/html5/thumbnails/23.jpg)
FETAL WEIGHT 48HR AFTER INFUSION
Gestation 48h Glucose infusion
Experimental Timeline Surgery Evaluation
• N = 57 pups/group, 10 moms, *p<0.05
Control HG0.5
0.6
0.7
0.8
0.9
1.0
Fetal weight 48 after infusion
Groups
Rat
io
*
![Page 24: FETAL HYPERGLYCEMIA AND HYPERINSULINEMIA …...fetal hyperglycemia and hyperinsulinemia program tissue-specific postnatal insulin resistance. disclosure](https://reader030.vdocuments.us/reader030/viewer/2022040201/5e468cdb0a3b3c056a46e3e3/html5/thumbnails/24.jpg)
FETAL GLUCOSE AND INSULIN LEVEL
Gestation 48h Glucose infusion
Experimental Timeline Surgery Evaluation
• N = 9 vs 7 pups/group, 4 moms
Control HG0
50
100
150
200
250
Fetal Serum Glucose Level
Groups
• N = 9 vs 7 pups/group, 4 moms
• P<0.05
![Page 25: FETAL HYPERGLYCEMIA AND HYPERINSULINEMIA …...fetal hyperglycemia and hyperinsulinemia program tissue-specific postnatal insulin resistance. disclosure](https://reader030.vdocuments.us/reader030/viewer/2022040201/5e468cdb0a3b3c056a46e3e3/html5/thumbnails/25.jpg)
FETAL GLUCOSE AND INSULIN LEVEL
Gestation 48h Glucose infusion
Experimental Timeline Surgery Evaluation
• N = 9 vs 7 pups/group, 4 moms
Control HG0
2
4
6
8
Fetal Insulin Level
Groups
Insu
lin le
vel (
ng/m
l)
Control HG0
50
100
150
200
250
Fetal Serum Glucose Level
Groups
• N = 9 vs 7 pups/group, 4 moms
• P<0.05
![Page 26: FETAL HYPERGLYCEMIA AND HYPERINSULINEMIA …...fetal hyperglycemia and hyperinsulinemia program tissue-specific postnatal insulin resistance. disclosure](https://reader030.vdocuments.us/reader030/viewer/2022040201/5e468cdb0a3b3c056a46e3e3/html5/thumbnails/26.jpg)
FETAL GLUCOSE AND RESPONSE TO INSULIN
Gestation 48h Glucose infusion
Experimental Timeline Surgery ±Insulin
• N = 13-17 pups/group, 4 moms, P<0.05
• N = 2-4 pups/group, 1mom, linear regression significant
![Page 27: FETAL HYPERGLYCEMIA AND HYPERINSULINEMIA …...fetal hyperglycemia and hyperinsulinemia program tissue-specific postnatal insulin resistance. disclosure](https://reader030.vdocuments.us/reader030/viewer/2022040201/5e468cdb0a3b3c056a46e3e3/html5/thumbnails/27.jpg)
FETAL HYPERINSULINEMIA DOES NOT CHANGE FETAL WEIGHT
Gestation 48 hour
Experimental Timeline EvaluationLong acting insulin
![Page 28: FETAL HYPERGLYCEMIA AND HYPERINSULINEMIA …...fetal hyperglycemia and hyperinsulinemia program tissue-specific postnatal insulin resistance. disclosure](https://reader030.vdocuments.us/reader030/viewer/2022040201/5e468cdb0a3b3c056a46e3e3/html5/thumbnails/28.jpg)
FETAL GLUCOSE LEVEL AND RESPONSE TO EXOGENOUS INSULIN
Gestation 48 hour
Experimental Timeline EvaluationLong acting insulin