Diabetes Mellitus 101 for
Medical Professionals
An Aggressive Pathophysiologic Approach to
Cardiometabolic Therapy for Type 2 Diabetes:
Part 6
Stan Schwartz MD,FACP
Clinical Associate Professor of Medicine, U of Pa.
Cardiometabolic Institute
Penn-Presbyterian Hospital, UPHS
Problems for animals in the wild
Modern Insulin Resistant Man “Locked” Into
Seasonal Insulin Resistance Syndrome Physiology
(Neuroendocrinology; Winter Condition All Year Long)
Insulin resistance begets insulin resistance: hyperinsulinemia in hypothalamus reduces nutrient sensing via increased NE/5HT, overcoming
normal spring rise in dopa/decreasing dopa in spring
ADAPTIVE Insulin Resistance
MAL-ADAPTIVE Insulin Resistance
Cincotta AH. et al. Taylor and Francis, Eds Hansen, B Shafrir, E London. 2002. 271-312. Meier AH, Cincotta AH et al. Diabetes
Reviews. 1996. 4(4):464-86.
The Biologic Clock
Integrator of Signals
SummerUses DOPAMINE
Winter
SCN
Low Dopa Set
High Dopa Set
PM-Winter
AM-Summer
Maladaptive
Low IR
Low Sympathetic
tone
Hyperglycemia,
high fat/sugar diets,
altered sleep/wake cycles,
no exercise, stress
High IR
High Sympathetic tone
Persistent
patients with genetically
susceptible b-cell
Diabetes Mellitus
Bromocryptine QR:
Proposed mechanism of action
Morning administration
(within 2 hours
of waking) of AGENT
Corrects
Low dopaminergic tone in
hypothalamus in early morning in
diabetes
Sympathetic tone
HPA axis tone
 Hepatic gluconeogenesis
 FFA and TG
 Insulin resistance
 Inflammation/hypercoagulation
Impaired glucose metabolism, hyperglycemia and
insulin resistance
Adverse cardiovascular pathology
Restoration of morning peak in
dopaminergic activity (via D2
receptor-mediated activity)
Sympathetic tone
HPA axis tone
 Hepatic gluconeogenesis
 FFA and TG
 Insulin resistance
 Inflammation/hypercoagulation
Decreased postprandial glucose levels
Reduction in insulin resistance
Day-long reduction in plasma glucose, TGs and FFAs
Fonseca. Use of Dopamine agonists in Type-2-Diabetes. Oxford American Pocket Cards. OUP, 2010
Cincotta. Hypothalamic role in Insulin Resistance and insulin Resistance Syndrome. Frontiers in Animal Diabetes Research Series. Taylor and Francis, Eds Hansen
B Shafrir, E London, pp 271-312, 2002
5
Bromocriptine-QR (Cycloset)
Dosing: Start with 0.8 mg (one tablet) within two hours of awakening in the AM.
Increase weekly as tolerated to target dose of 1.6 to 4.8 mg upon awakening
Holt RIG, et al. Diabetes, Obesity and Metabolism 12: 1048–57, 2010
KM Curve – Fast-Acting Bromocryptine Safety Trial
Cumulative Percent Composite CVD Endpoint
HR 0.58; 95% CI, 0.35-0.96
RRR=42%
*MI, Stroke, hospitalization unstable angina, hospitalization CHF, or coronary revasc.
KM Curve: the separation in favor of Cycloset begins 3 months and persists through the end of the study
Gaziano M. Diabetes Care 2010, March 23 online
Colsevelam
in Prediabetes
Handelsman
Effects of Colesevelam on A1C Levels
in Add-On Therapy Trials: ≥0.50% Reductions
-0.10
GLOWS
Week 12
Metformin
Week 26
Sulfonylurea
Week 26
Insulin
Week 16
Mean Change
in A1C (%)
-0.20
*P≤0.007
-0.30
n=>1,000
-0.40
-0.50
-0.50*
-0.60
-0.50*
-0.54*
Zieve FJ et al. Clin Ther. 2007;29:74.
Bays H et al. Presented at: AACE 16th Annual Meeting & Clinical Congress; April 2007. Abstract 204.
Fonseca VA et al. Presented at: AACE 16th Annual Meeting & Clinical Congress; April 2007. Abstract 409.
Goldberg RB, Truitt K. Presented at: AHA Scientific Sessions; November 2006; Chicago, IL. Poster 1581.
-0.54*