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Does Making too much Insulin
Cause Type 2 Diabetes?
Thomas A. Buchanan, MD
For the
USC Gestational Diabetes Study Group
Teach you something about the biology,
prediction and prevention of type 2 diabetes
Show you what an interdisciplinary tea...
The USC Gestational Diabetes Study Group
Research Staff
Enrique Trigo
Karla Garcia
Lilit Baronikian
Miwa Kawakubo
Aura Mar...
Gestational Diabetes
Population Screening for Mild
Hyperglycemia
Definition
Glucose intolerance with onset or first recognition
during pregnancy
Gestational Diabetes Mellitus
Detection
Sc...
Circulating Glucose
Frequency
No GDM GDM
Gestational Diabetes
Population Perspective
0
10
20
30
40
50
60
70
80
5 10 15 20 25 30
 







 Navajo
o
o
o
o
o
o
o Zuni
Mixed/Other
Hispanic (USC)
x
x
x
...
Multifaceted Approach to Diabetes after GDM
USC Gestational Diabetes Study Group
Clinical Cohort
Women followed in standar...
Defining Diabetes Incidence and Clinical Risk Factors
Subjects: Hispanic women with GDM who delivered at
Womens Hospital (...
Kjos et al: Diabetes 44:586-591, 1994
Diabetes after GDM
Cumulative Incidence in Clinical Cohort
Years Postpartum
Cumulati...
Diabetes after GDM
Risk Factors in Clinical Cohort
At Baseline (pregnancy and immediate postpartum)
Early gestational age ...
Identifying Physiological Determinants of Diabetes
Subjects: Prospectively recruited cohort of Hispanic women
with GDM who...
USC GDM Cohort Study
Overview of Study Design
Hispanic American women
GDM by 3rd
GDM Workshop
criteriaIslet cell antibody ...
Gestational Diabetes Mellitus
Multiple Metabolic Defects during the Third Trimester
Xiang et al: Diabetes 48:848-854, 1999...
Type 2 Diabetes after GDM
Cumulative Incidence in Physiological Cohort
Xiang et al: Diabetes 59:2652-2630, 2010
n=72 with
...
Resistant Sensitive
Regulation of Blood Glucose
Normal
Diabetic
Impaired
Insulin Sensitivity
InsulinSecretion Insulin Sens...
0 1 2 3
0
200
400
600
800
Insulin Sensitivity (SI)
AcuteInsulinResponse
Yes (n=24) No (n=47)Diabetes:
Xiang et al: Diabete...
Declining β-cell Function after GDM
Relation to Glucose Levels
Prior GDMs (n=71): OGTTs and IVGTTs at 15, 30, 45, 60, 75 m...
What predicts diabetes?
Evolution of Hyperglycemia after GDM
What predicts diabetes?
5-11-05
0 200 400 600 800 1000
0
100
200
300
Disposition Inde...
What predicts falling
β-cell compensation?
Subjects: n=60 with at least two visits by 75 months
Baseline Variables: body mass and fat, glucose levels,
insulin levels...
Only Independent Correlate: Weight Gain (p=0.003)
Results
Predicting Falling β-cell Function
Xiang et al: Diabetes Care 33...
Progressive β-cell Failure
Type 2 Diabetes
How might obesity affect β-cell function?
Insulin Resistance
Obesity
Fatty Acid...
Strongest Correlate: Weight Gain (p=0.003)
“Explained” by three independent changes:
Adjust for:
Impact on
regression Resi...
Progressive β-cell Failure
Type 2 Diabetes
How might obesity affect β-cell function?
Insulin Resistance
Obesity
Fatty Acid...
Can we do anything to stop
progression to diabetes?
Feasibility and Mechanisms for Diabetes Prevention
Subjects: Prospective cohort of women Hispanic with prior
GDM (n=266)
S...
Preventing Type 2 Diabetes
Three Levels of Opportunity
Adipose
Tissue
Liver &
Muscle
Adipokines
Fatty Acids
Insulin Resist...
Overview of Design: Diabetes Prevention
TRoglitazone In Prevention Of Diabetes: TRIPOD Study
Buchanan et al: Diabetes 51:2...
TRIPOD Study: Diabetes Rates
Months on Study
PeoplewithDiabetes
60%
40%
20%
0%
0 10 20 30 40 50 60
Placebo
Troglitazone
55...
On Trial
Off
Trial
Months after Randomization
FractionwithDiabetes
60%
40%
20%
0%
0 20 40 60
Placebo
12.1% per year
Trogli...
p=0.01 between groups
Baseline 8 Months Post-trial
Placebo (n=40)
0 2 4 6
MINMOD SI
AcuteInsulinResponse
(uU/mlxmin)
200
4...
Overview of Integrated Design
Off
drug
Open Label Pioglitazone
PIPOD Trial
2004
TRIPOD and PIPOD
2000 - 20011995
Off
drug
...
0 2 4 6 8
0
400
800
1200
1600
DispositionIndex
(SIxAIRg)
Years
Effect of Pioglitazone after Placebo
β-cell Function in TRI...
0 2 4 6 8
0
400
800
1200
1600
DispositionIndex
(SIxAIRg)
Years
Effect of Pioglitazone after Troglitazone
β-cell Function i...
Type 2 Diabetes Prevention
Results of Recent Randomized Trials
Study Subjects Intervention Rel. Risk
*Similar β-cell prote...
Reducing body fat or mitigating its biological
consequences provides the best evidence for
disease modification (β-cell pr...
What is the mechanism for
diabetes prevention with TZDs?
Overview of Design: Diabetes Prevention
TRoglitazone In Prevention Of Diabetes: TRIPOD Study
Hispanic women
with prior GDM...
Resistant Sensitive
Insulin Sensitivity
InsulinOutputTRIPOD: β-cell “Rest” and Protection from Diabetes
Baseline 3 Months
...
Resistant Sensitive
Insulin Sensitivity
InsulinOutput β-cell Protection in TRIPOD
Baseline
3 Months
Diabetes
6% / yr
Diabe...
-40 -20 0 20 40 60
0
5
10
15
Piogiltazone
Initial Reduction in Insulin Output*
(% of Basal)
DiabetesIncidence(%/yr)
TRIPOD...
Some Attractive Mechanisms
“Toxic” Effects of β-cell Loading
Unfolded protein response
insulin
Amylin (IAPP)
Oxidative str...
β-cell Mass
Neogenesis
Replication
Hypertrophy
}Gain
Necrosis
Apoptosis
Loss
Recruitment
Synthesis Stimulus
Secretion
Coup...
Genetic Determinants of GDM and Type 2 Diabetes
Subjects: Mexican American GDM and control probands and
family members rec...
Where do we go from here?
New Research Directions
Gestational Diabetes Study Group
Impact of GDM on obesity and glucose regulation in
offspring: Kat...
Prevention and Early Treatment of Type 2 Diabetes
One Clinical Strategy
Measure Glucose
Diabetes
Diet+Exercise
and Medicat...
β-cells fail when they are exposed to obesity and
insulin resistance.
“Overload” appears to be an important mechanism
cont...
Thank You!
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Does making too much insulin cause type 2 diabetes? Slide 1 Does making too much insulin cause type 2 diabetes? Slide 2 Does making too much insulin cause type 2 diabetes? Slide 3 Does making too much insulin cause type 2 diabetes? Slide 4 Does making too much insulin cause type 2 diabetes? Slide 5 Does making too much insulin cause type 2 diabetes? Slide 6 Does making too much insulin cause type 2 diabetes? Slide 7 Does making too much insulin cause type 2 diabetes? Slide 8 Does making too much insulin cause type 2 diabetes? Slide 9 Does making too much insulin cause type 2 diabetes? Slide 10 Does making too much insulin cause type 2 diabetes? Slide 11 Does making too much insulin cause type 2 diabetes? Slide 12 Does making too much insulin cause type 2 diabetes? Slide 13 Does making too much insulin cause type 2 diabetes? Slide 14 Does making too much insulin cause type 2 diabetes? Slide 15 Does making too much insulin cause type 2 diabetes? Slide 16 Does making too much insulin cause type 2 diabetes? Slide 17 Does making too much insulin cause type 2 diabetes? Slide 18 Does making too much insulin cause type 2 diabetes? Slide 19 Does making too much insulin cause type 2 diabetes? Slide 20 Does making too much insulin cause type 2 diabetes? Slide 21 Does making too much insulin cause type 2 diabetes? Slide 22 Does making too much insulin cause type 2 diabetes? Slide 23 Does making too much insulin cause type 2 diabetes? Slide 24 Does making too much insulin cause type 2 diabetes? Slide 25 Does making too much insulin cause type 2 diabetes? Slide 26 Does making too much insulin cause type 2 diabetes? Slide 27 Does making too much insulin cause type 2 diabetes? Slide 28 Does making too much insulin cause type 2 diabetes? Slide 29 Does making too much insulin cause type 2 diabetes? Slide 30 Does making too much insulin cause type 2 diabetes? Slide 31 Does making too much insulin cause type 2 diabetes? Slide 32 Does making too much insulin cause type 2 diabetes? Slide 33 Does making too much insulin cause type 2 diabetes? Slide 34 Does making too much insulin cause type 2 diabetes? Slide 35 Does making too much insulin cause type 2 diabetes? Slide 36 Does making too much insulin cause type 2 diabetes? Slide 37 Does making too much insulin cause type 2 diabetes? Slide 38 Does making too much insulin cause type 2 diabetes? Slide 39 Does making too much insulin cause type 2 diabetes? Slide 40 Does making too much insulin cause type 2 diabetes? Slide 41 Does making too much insulin cause type 2 diabetes? Slide 42 Does making too much insulin cause type 2 diabetes? Slide 43 Does making too much insulin cause type 2 diabetes? Slide 44 Does making too much insulin cause type 2 diabetes? Slide 45 Does making too much insulin cause type 2 diabetes? Slide 46 Does making too much insulin cause type 2 diabetes? Slide 47 Does making too much insulin cause type 2 diabetes? Slide 48 Does making too much insulin cause type 2 diabetes? Slide 49 Does making too much insulin cause type 2 diabetes? Slide 50 Does making too much insulin cause type 2 diabetes? Slide 51
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Presented at the Keck School of Medicine of USC Research Seminar in October 2011. Learn more about Tom's latest work: http://profiles.sc-ctsi.org/thomas.buchanan

Does making too much insulin cause type 2 diabetes?

  1. 1. Does Making too much Insulin Cause Type 2 Diabetes? Thomas A. Buchanan, MD For the USC Gestational Diabetes Study Group
  2. 2. Teach you something about the biology, prediction and prevention of type 2 diabetes Show you what an interdisciplinary team working in humans can accomplish Goals
  3. 3. The USC Gestational Diabetes Study Group Research Staff Enrique Trigo Karla Garcia Lilit Baronikian Miwa Kawakubo Aura Marroquin Cesar Ochoa Jose Goico Sylvia Tan Investigators Tom Buchanan Siri Kjos Richard Watanabe Stan Azen Anny Xiang Ruth Peters Hooman Allayee Jean Lawrence Katie Page Penina Segall-Gutierrez Jorge Caro George Aurea Isabel Enriquez Participants: GDM Cohort Study, TRIPOD and PIPOD Studies, BetaGene Study With Strong Support from: Funding: NIDDK, NCRR/GCRC/CTSI, ADA, Parke-Davis, Takeda Collaborators: Bergman group, Howard Hodis, Wendy Mack, Goran group
  4. 4. Gestational Diabetes Population Screening for Mild Hyperglycemia
  5. 5. Definition Glucose intolerance with onset or first recognition during pregnancy Gestational Diabetes Mellitus Detection Screen pregnant women not known to have diabetes: for at-risk clinical characteristics for diagnostic oral glucose tolerance “Population” screening for elevated glucose levels in young womenGlucose levels that might cause fetal morbidity
  6. 6. Circulating Glucose Frequency No GDM GDM Gestational Diabetes Population Perspective
  7. 7. 0 10 20 30 40 50 60 70 80 5 10 15 20 25 30           Navajo o o o o o o o Zuni Mixed/Other Hispanic (USC) x x x x x x x x x x Boston Cohort Years after Delivery CumulativeIncidenceofDiabetes(%) Diabetes After GDM Kim et al: Diabetes Care, 2002
  8. 8. Multifaceted Approach to Diabetes after GDM USC Gestational Diabetes Study Group Clinical Cohort Women followed in standard clinical care with annual testing for diabetes after index pregnancy Main Outcomes: diabetes incidence and clinical risk factors Physiological Cohort Women followed with detailed physiological testing during pregnancy and at 15- month intervals thereafter Main Outcomes: physiological mechanisms for development of diabetes Interventional Cohort Women enrolled in clinical trials of diabetes prevention and early treatment Main Outcomes: feasibility and mechanisms for diabetes prevention Genetic Cohort GDM and control probands and their families studied with detailed physiological and morphological phenotyping and genetic analysis Main Outcomes: genetic associations with diabetes quantitative traits
  9. 9. Defining Diabetes Incidence and Clinical Risk Factors Subjects: Hispanic women with GDM who delivered at Womens Hospital (n=700-1000) Setting: Outpatient clinic where women returned for diabetes testing postpartum and annually Design: Observational Main Outcomes: diabetes incidence rate and clinical risk factors for diabetes Investigators: Siri Kjos, Anny Xiang, Ruth Peters, Tom Buchanan Support: faculty blood, sweat and tears! Clinical Cohort
  10. 10. Kjos et al: Diabetes 44:586-591, 1994 Diabetes after GDM Cumulative Incidence in Clinical Cohort Years Postpartum CumulativeIncidence(%) 0 20 40 80 60 0 1 2 3 4 5 6 n=671
  11. 11. Diabetes after GDM Risk Factors in Clinical Cohort At Baseline (pregnancy and immediate postpartum) Early gestational age at diagnosis1 High glucose levels1 During Follow-up Weight gain2 Additional pregnancy2 Progestin-only contraception3,4 1 Kjos et al: Diabetes 44:586-591, 1995, 2 Peters et al: Lancet 347:227-230, 1996 3 Kjos et al: JAMA 280:533-538, 1998, 4 Xiang et al: Diabetes Care 29:613-617, 2006 Insulin Resistance } Hypothesis: Insulin resistance is causing β-cell failure
  12. 12. Identifying Physiological Determinants of Diabetes Subjects: Prospectively recruited cohort of Hispanic women with GDM who delivered at Womens Hospital (n=150) Setting: GCRC-based study Design: Observational - detailed physiological measurements of glucose regulation during pregnancy and at 15-month intervals thereafter Main Outcomes: physiological changes that predict or attend the development of diabetes Investigators: Tom Buchanan, Anny Xiang, Ruth Peters, Siri Kjos Support: NIH R01 DK46374 (1993-2007) Physiological Cohort
  13. 13. USC GDM Cohort Study Overview of Study Design Hispanic American women GDM by 3rd GDM Workshop criteriaIslet cell antibody negative Detailed Metabolic Measurements Glucose levels Insulin resistance β-cell function Body composition 15 30 45 60 75 900 Months After Delivery 3rd TM Non-Pregnant 105 120 132 144 n=150 GDM n=30 Control
  14. 14. Gestational Diabetes Mellitus Multiple Metabolic Defects during the Third Trimester Xiang et al: Diabetes 48:848-854, 1999 Beta Cell Compensation 1500 1000 500 0 GDMControl DispositionIndex p<0.0001 IVGTT Skeletal Muscle Control (30) GDM (150) Adipose Tissue Control GDM Liver Control GDM
  15. 15. Type 2 Diabetes after GDM Cumulative Incidence in Physiological Cohort Xiang et al: Diabetes 59:2652-2630, 2010 n=72 with multiple visits
  16. 16. Resistant Sensitive Regulation of Blood Glucose Normal Diabetic Impaired Insulin Sensitivity InsulinSecretion Insulin Sensitivity and Secretion Bergman et al: J Clin Invest, 1981 Normal Abnormal Sensitivity x Output = Constant “Disposition Index” Disposition Index 2000 1000 200
  17. 17. 0 1 2 3 0 200 400 600 800 Insulin Sensitivity (SI) AcuteInsulinResponse Yes (n=24) No (n=47)Diabetes: Xiang et al: Diabetes 55:1074-1079, 2006 Longitudinal Changes: First Five Years β-cell Function after GDM 3.9 years 3.7 years
  18. 18. Declining β-cell Function after GDM Relation to Glucose Levels Prior GDMs (n=71): OGTTs and IVGTTs at 15, 30, 45, 60, 75 months postpartum Yes (n=24)No (n=47)Diabetes: Diabetes 0 200 400 600 800 1000 0 100 200 Disposition Index mg/dl Fasting Glucose 0 200 400 600 800 1000 0 100 200 300 Disposition Index mg/dl Diabetes Yes (n=24)No (n=47)Diabetes: OGTT 2hr Glucose Xiang et al: Diabetes 55:1074-1079, 2006 5-11-05
  19. 19. What predicts diabetes?
  20. 20. Evolution of Hyperglycemia after GDM What predicts diabetes? 5-11-05 0 200 400 600 800 1000 0 100 200 300 Disposition Index mg/dl Diabetes Yes (n=24)No (n=47)Diabetes: OGTT 2hr Glucose Answer: characteristics of people who almost have diabetes (PLUS: falling β-cell function, weight gain, pregnancy, progestins)
  21. 21. What predicts falling β-cell compensation?
  22. 22. Subjects: n=60 with at least two visits by 75 months Baseline Variables: body mass and fat, glucose levels, insulin levels, insulin resistance, β-cell compensation, lipid levels (FFA and clinical lipids), adipocytokines During Follow-up: pregnancy; hormonal contraception; weight and fat gain; change in insulin sensitivity, lipids, adipocytokines Analysis: Random coefficients mixed modeling to identify factors predictive of (for baseline variables) or associated with (for follow-up variables) change β-cell compensation Predicting Falling β-cell Function Design
  23. 23. Only Independent Correlate: Weight Gain (p=0.003) Results Predicting Falling β-cell Function Xiang et al: Diabetes Care 33:396-401, 2010 How does it work?
  24. 24. Progressive β-cell Failure Type 2 Diabetes How might obesity affect β-cell function? Insulin Resistance Obesity Fatty Acids Adipokines Glucose Toxicity
  25. 25. Strongest Correlate: Weight Gain (p=0.003) “Explained” by three independent changes: Adjust for: Impact on regression Residual p-value Falling SI -40% <0.04 Falling Adiponectin -19% <0.02 Rising CRP -19% <0.02 All three -70% <0.29 Adipoiknes may directly influence the propensity for β-cells to fail. Results Predicting Changing β-cell Function Xiang et al: Diabetes Care 33:396-401, 2010
  26. 26. Progressive β-cell Failure Type 2 Diabetes How might obesity affect β-cell function? Insulin Resistance Obesity Fatty Acids Adipokines Glucose Toxicity Χ
  27. 27. Can we do anything to stop progression to diabetes?
  28. 28. Feasibility and Mechanisms for Diabetes Prevention Subjects: Prospective cohort of women Hispanic with prior GDM (n=266) Setting: GCRC-based study Design: Interventional clinical trial with detailed physiological measurements Main Outcomes: diabetes rates and mechanisms for diabetes prevention and beta cell preservation; pre-clinical atherosclerosis Investigators: Tom Buchanan, Anny Xiang, Ruth Peters, Stan Azen, Howard Hodis, Wendy Mack Support: Investigator-initiated pharmaceutical grants (Parke- Davis and Takeda), NIH and ADA supplemental funding Prevention Cohort
  29. 29. Preventing Type 2 Diabetes Three Levels of Opportunity Adipose Tissue Liver & Muscle Adipokines Fatty Acids Insulin Resistance 2 Insulin Resistance 1 Obesity Energy Balance Negative Positive Weight Loss and Wasting Fat Accumulation 3 β-cell Failure Weak B-cells Hyperglycemia Robust B-cells Hyperinsulinemia TZDs
  30. 30. Overview of Design: Diabetes Prevention TRoglitazone In Prevention Of Diabetes: TRIPOD Study Buchanan et al: Diabetes 51:2796-2803, 2002 Hispanic women with prior GDM 2000 - 20011995 Off drug Blinded Troglitazone Blinded Placebo TRIPOD Trial Age: 34 yrs BMI: 30 kg/m2 Fasting glucose: 98 mg/dl 2-hr Glucose: 154 mg/dl HbA1C: 5.7% OGTTs: Diabetes IVGTTs: Insulin Resistance β-cell Function
  31. 31. TRIPOD Study: Diabetes Rates Months on Study PeoplewithDiabetes 60% 40% 20% 0% 0 10 20 30 40 50 60 Placebo Troglitazone 55% Relative Risk Reduction Buchanan et al: Diabetes 51:2796-2803, 2002
  32. 32. On Trial Off Trial Months after Randomization FractionwithDiabetes 60% 40% 20% 0% 0 20 40 60 Placebo 12.1% per year Troglitazone 5.4% per year 21% per yearn=40 3% per year n=44 ivGTT Masking? TRIPOD Study: Post-Trial Washout Buchanan et al: Diabetes 51:2796-2803, 2002
  33. 33. p=0.01 between groups Baseline 8 Months Post-trial Placebo (n=40) 0 2 4 6 MINMOD SI AcuteInsulinResponse (uU/mlxmin) 200 400 600 800 0 0 2 4 6 MINMOD SI Troglitazone (n=44) 39% fall Women without Diabetes during Trial Stable TRIPOD: Preservation of β-cell Function Diabetes Prevention Buchanan et al: Diabetes 51:2796-2803, 2002
  34. 34. Overview of Integrated Design Off drug Open Label Pioglitazone PIPOD Trial 2004 TRIPOD and PIPOD 2000 - 20011995 Off drug Blinded Troglitazone Blinded Placebo TRIPOD Trial Diabetes Diabetes Open Label Troglitazone Open Label Troglitazone OGTTs IVGTTs Xiang et al: Diabetes 55:517-522, 2006
  35. 35. 0 2 4 6 8 0 400 800 1200 1600 DispositionIndex (SIxAIRg) Years Effect of Pioglitazone after Placebo β-cell Function in TRIPOD+PIPOD n=32 Pioglitazone PIPOD p=0.14 OffPlacebo TRIPOD p=0.003 Off Xiang et al: Diabetes 55:517-522, 2006
  36. 36. 0 2 4 6 8 0 400 800 1200 1600 DispositionIndex (SIxAIRg) Years Effect of Pioglitazone after Troglitazone β-cell Function in TRIPOD+PIPOD n=27 Troglitazone TRIPOD p=0.24 Off Pioglitazone PIPOD p=0.12 Off Xiang et al: Diabetes 55:517-522, 2006
  37. 37. Type 2 Diabetes Prevention Results of Recent Randomized Trials Study Subjects Intervention Rel. Risk *Similar β-cell protection with pioglitazone Finnish DPS I.G.T. Lifestyle 58% U.S. DPP I.G.T. Lifestyle 58% XENDOS I.G.T. Orlistat 45% Weight Loss Stop-NIDDM I.G.T. Acarbose 25% Metformin 31%U.S. DPP I.G.T.Glucose Absorption, Production TRIPOD Prior GDM Troglitazone 55%* DREAM I.G.T. Rosiglitazone 62% Fat-induced Ins. Resist. ACT NOW I.G.T. Pioglitazone 72%
  38. 38. Reducing body fat or mitigating its biological consequences provides the best evidence for disease modification (β-cell protection) in “pre- diabetes”. Diabetes Prevention Trials Important Lesson
  39. 39. What is the mechanism for diabetes prevention with TZDs?
  40. 40. Overview of Design: Diabetes Prevention TRoglitazone In Prevention Of Diabetes: TRIPOD Study Hispanic women with prior GDM 2000 - 20011995 Off drug Blinded Troglitazone Blinded Placebo TRIPOD Trial Age: 34 yrs BMI: 30 kg/m2 Fasting glucose: 98 mg/dl 2-hr Glucose: 154 mg/dl HbA1C: 5.7% OGTTs: Diabetes IVGTTs: Insulin Resistance β-cell Function Buchanan et al: Diabetes 51:2796-2803, 2002
  41. 41. Resistant Sensitive Insulin Sensitivity InsulinOutputTRIPOD: β-cell “Rest” and Protection from Diabetes Baseline 3 Months β-cell “Rest” = Protection From Diabetes 10%/yr Diabetes n=35 6%/yr Diabetes n=31 0%/yr Diabetes n=42 (IVGTTInsulinArea) (MINMOD SI) Troglitazone 12%/yr Diabetes Placebo Buchanan et al: Diabetes 51:2796-2803, 2002
  42. 42. Resistant Sensitive Insulin Sensitivity InsulinOutput β-cell Protection in TRIPOD Baseline 3 Months Diabetes 6% / yr Diabetes 0% / yr (IVGTTInsulinArea) (MINMOD SI) Buchanan et al: Diabetes, 2002 Fasting Glucose -7% -3% p=0.01 Fasting FFA -2% -8% p=0.17 Triglycerides -17% -19% p=0.60 Is it really “unloading” that counts?
  43. 43. -40 -20 0 20 40 60 0 5 10 15 Piogiltazone Initial Reduction in Insulin Output* (% of Basal) DiabetesIncidence(%/yr) TRIPOD and PIPOD β-cell “Rest” and Diabetes Rates Troglitazone *change in IVGTT insulin area, in tertilesXiang et al: Diabetes 55:517-522, 2006
  44. 44. Some Attractive Mechanisms “Toxic” Effects of β-cell Loading Unfolded protein response insulin Amylin (IAPP) Oxidative stress Direct amylin toxicity All may increase apoptosis and impair insulin secretion
  45. 45. β-cell Mass Neogenesis Replication Hypertrophy }Gain Necrosis Apoptosis Loss Recruitment Synthesis Stimulus Secretion Coupling Insulin Secretion Circulating Insulin Hepatic Extraction Expansion Signals GeneticsDrugs? Insulin Resistance Obesity Genetics? “Loading” Adipokines Χ+ Main Targets for Disease Modification in β-cells
  46. 46. Genetic Determinants of GDM and Type 2 Diabetes Subjects: Mexican American GDM and control probands and family members recruited from a variety of sources across Los Angeles (n=~2200) Setting: GCRC-base study Design: Cross-sectional with longitudinal sub-study Main Outcomes: associations between putative diabetes genes and intermediate phenotypes for glucose regulation Investigators: Tom Buchanan, Richard Watanabe, Anny Xiang, Hooman Allayee, Jean Lawrence Support: NIH R01s and ADA clinical research grants Genetic Cohort
  47. 47. Where do we go from here?
  48. 48. New Research Directions Gestational Diabetes Study Group Impact of GDM on obesity and glucose regulation in offspring: Katie Page (CTSI K12 Scholar) Enhancing compliance with follow-up for detection and prevention of diabetes: Penina Segall-Gutierrez (CDC research grant) Bariatric surgery and β-cell preservation: Tom Buchanan, Anny Xiang, Namir Katkhouda, Elizabeth Beale (planning) Ethnic differences in glucose regulation after GDM: Anny Xiang, Tom Buchanan (planning)
  49. 49. Prevention and Early Treatment of Type 2 Diabetes One Clinical Strategy Measure Glucose Diabetes Diet+Exercise and Medication Diabetic Higher Risk Diet and Exercise Impaired Continue Diet and Exercise Stable Glycemia Medication DevelopsD iabetes Lower Risk Normal Diet and Exercise Annual Follow-up Prevention Treatment High Risk Individual
  50. 50. β-cells fail when they are exposed to obesity and insulin resistance. “Overload” appears to be an important mechanism contributing to β-cell failure. Unloading can preserve β-cell function and prevent diabetes. Weight loss and TZDs are the best approaches we have right now – but not perfect. We have to do something big about obesity if we are to have any profound impact this problem. Clinical and translational research is a great way to do science with your friends and have a real impact on human health. Summary
  51. 51. Thank You!
  • AngelaPerez763389

    Dec. 1, 2021
  • jessicafaustor

    Sep. 8, 2015

Presented at the Keck School of Medicine of USC Research Seminar in October 2011. Learn more about Tom's latest work: http://profiles.sc-ctsi.org/thomas.buchanan

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