1. WHAT ABOUT COMPLICATIONS OF DIABETES?
ANOTHER INSIGHT:
WHAT ABOUT COMPLICATIONS OF DIABETES?
We noticed 2 ‘old’ general principles:

2. Pathophysiology of complications are THE SAME AS THOSE THAT DAMAGE THE Beta-Cell* * * *

3. Pathophysiology of Diabetic Complications: Old Conundrum : why similar HgA1c in different folk give different risks I
Metabolic Disorder
Glucose, insulin hormones, enzymes, metabolites, etc (i.e., control) II
Individual Susceptibility
Genetic/ethnic
?Acquired
III
Modulating Factors
Hypertension, diet, smoking, etc.
Delayed Complications
Retinal, renal neural, cardiovascular, cutaneous, etc. IV
Early V
Late
Point of metabolic “no return”
harry keen, chronic complications of diabetes mellitus, chapter 16, in monograph, ed. Galloway et al DM, lilly research labs, 1988

4. A Unifying Pathophysiologic Approach to The Complications of Diabetes in the Context of the Beta-cell Classification of Diabetes
ALL COMPLICATIONS
(Micro/MacroVascular
Damage)
Susceptibility to abnormal metab. envir.
Genes
(Some in common/
Some
Different)
Endogenous
Fuel Excess
(glucose/ lipids)
(Brownlee’s Unified Theory of Complications
Insulin Resistance
Metab. Syn, BP, Lipid
Circulating master metabolic REDOX regulators
(L/P, β/A, SH/SS, ROS)
miRNA
Inflam./
Immune Mech.
Epigenetics
Environ
ment
Legend: The Primary Cause of the Complications of Diabetes is the damage wrought by Hyperglycemia and other excess fuels engendered by reduced insulin or insulin effect due to abnormal beta-cell function, primarily in tissues not dependent on insulin for glucose transport into the cell.
We note that the same pathophysiologic mechanisms that damage the beta-cell are also involved with (help define) the risk of developing the complications of diabetes.
The specific risk of developing complications even with similar degrees of hyperglycemia depend on genetic susceptibility to damage by the abnormal metabolic environment, , exogenous environmental factors, immune/ inflammatory factors and insulin resistance and the metabolic syndrome genetically susceptible beta cells are damaged by environmental, inflammatory/immune mechanisms and IR /dysmetabolic syndrome factors. The resultant abnormal metabolic environment resulting from abnormal fuel excess (glucose, FFAs) can iteratively exacerbate beta cell dysfunction and damage genetically susceptible peripheral cells and tissues resulting in diabetic chronic complications. The presence or absence, or degree of damage is defined by the presence or absence of the same processes (environmental, inflammatory/immune mechanisms and IR /dysmetabolic syndrome factors) that are involved in beta cell dysfunction.
The The Fuel Excess resultant from abnormal b-cell function iteratively further exacerbate b-cell dysfunction. The pathways organized by Brownlee, acting through miRNAs, oxidative stress, Barabra Corkey’s metaboloic REDOX regulators as well as epigenetics further exacerbate IR, inflammation and immune dysfunction and ,potentially, susceptibility to environmental factors
Glucotoxicity /
lipotoxicity
Cause or permit susceptibility to damage
MOST MECHANISMS OF B-cell Damage Overlap with Causes of ALL Complications:
[ describe in 2 ways]

5. it’s CELLS/TISSUES affected by the pathophysiologic mechanisms
BTW: In Same Context of changing classification of DM, need to Change Classification/ Nomenclature of the Complications of Diabetes
In order to reflect:
‘Microvascular/ Macrovascular ‘ terminology have lost their meaning given new understanding of Causes of Complications-
it’s CELLS/TISSUES affected by the pathophysiologic mechanisms
Complications of ‘T1DM’ and T2DM’ are the same, not different

6. FUEL EXCESS- hyperglycemia/hyperlipidemia
Circulating master metabolic REDOX
Regulators L/P, β/A, SH/SS, ROS
L/P (lactate/pyruvate); b/A (b-hydroxybutyrate/acetoacetate); SH/SS (reduced thiol cysteine/oxidized thiol cyst)
Cascade of Mechanisms of Diabetes and its Complications: Complications are Cellular Based- not Vascular
FUEL EXCESS- hyperglycemia/hyperlipidemia
Acting via
Polyol flux, PKC, Hexosamine flux, AGE’s,
Transcription factors- Epigenetics
DNA methylation, Histone modifications
miRNA, Gene expression IncRNA
ROS, Altered REDOX regulators
Exacerbate: Insulin resistance/metabolic syndrome ,
inflammation/ immune system, environmental interactions
Acting on/ in
Susceptible Cell Types/ Tissues-
Beta-cells ,
Endothelium, Cardiomyocytes, Renal Cells, Retinal Cells,
Neurons, Vascular Smooth Muscle
All complications of Diabetes-
eye, kidney nerve, atherosclerosis
Worsening Beta- Cell Function
Adapted from: Evans, Brownlee, Corkey, P….

7. A Unifying Pathophysiologic Approach to The Complications of Diabetes in the Context of the Beta-cell Classification of Diabetes
Defines Logic for Varied Risk of Complications in Individual Patients with similar , (poor) HgA1: Likely Genetically based
ALL COMPLICATIONS
(Micro/MacroVascular
Damage)
Susceptibility to abnormal metab. envir.
Genes
(Some in common/
Some
Different)
Endogenous
Fuel Excess
(glucose/ lipids)
(Brownlee’s Unified Theory of Complications
Insulin Resistance
Metab. Syn, BP, Lipid
Circulating master metabolic REDOX regulators
(L/P, β/A, SH/SS, ROS)
miRNA
Inflam./
Immune Mech.
Epigenetics
Environ
ment
Legend: The Primary Cause of the Complications of Diabetes is the damage wrought by Hyperglycemia and other excess fuels engendered by reduced insulin or insulin effect due to abnormal beta-cell function, primarily in tissues not dependent on insulin for glucose transport into the cell.
We note that the same pathophysiologic mechanisms that damage the beta-cell are also involved with (help define) the risk of developing the complications of diabetes.
The specific risk of developing complications even with similar degrees of hyperglycemia depend on genetic susceptibility to damage by the abnormal metabolic environment, , exogenous environmental factors, immune/ inflammatory factors and insulin resistance and the metabolic syndrome genetically susceptible beta cells are damaged by environmental, inflammatory/immune mechanisms and IR /dysmetabolic syndrome factors. The resultant abnormal metabolic environment resulting from abnormal fuel excess (glucose, FFAs) can iteratively exacerbate beta cell dysfunction and damage genetically susceptible peripheral cells and tissues resulting in diabetic chronic complications. The presence or absence, or degree of damage is defined by the presence or absence of the same processes (environmental, inflammatory/immune mechanisms and IR /dysmetabolic syndrome factors) that are involved in beta cell dysfunction.
The The Fuel Excess resultant from abnormal b-cell function iteratively further exacerbate b-cell dysfunction. The pathways organized by Brownlee, acting through miRNAs, oxidative stress, Barabra Corkey’s metaboloic REDOX regulators as well as epigenetics further exacerbate IR, inflammation and immune dysfunction and ,potentially, susceptibility to environmental factors
Glucotoxicity /
lipotoxicity
Cause or permit susceptibility to damage

8. Phenotypic Presentation of Each Complication is defined by:
Slope = ‘Natural History’ over time,
i.e.= RATE OF Development of Comp. Slope is not linear, and may be intermittently relapsing, remitting, stabilized, and improved, until ‘point of no return’
when presence and damage irreversible
no Comp. − --
end Stage −
DEPENDENT on
Genes- which, how many
Environmental Factors-
which/how many
Inflamatory/ Immune- which factors/ how many
IR/ Cardiometabolic Syndrome
For All DM
Complication
Risk/Presence
Modifiable
Irreversible
Severity of Complication
I I I I I/ ≈ / I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I
Increasing Age/ Duration
Age/ at presentation = tipping point when the combined pathophysiolocic processes are exposed as phenotypic functional/structural abnormalities

9. A Unifying Pathophysiologic Approach to The Complications of Diabetes in the Context of the Beta-cell Classification of Diabetes
ALL COMPLICATIONS
(Micro/MacroVascular
Damage)
Susceptibility to abnormal metab. envir.
Genes
(Some in common/
Some
Different)
Endogenous
Fuel Excess
(glucose/ lipids)
(Brownlee’s Unified Theory of Complications
Insulin Resistance
Metab. Syn, BP, Lipid
Circulating master metabolic REDOX regulators
(L/P, β/A, SH/SS, ROS)
miRNA
Inflam./
Immune Mech.
Epigenetics
Environ
ment
Legend: The Primary Cause of the Complications of Diabetes is the damage wrought by Hyperglycemia and other excess fuels engendered by reduced insulin or insulin effect due to abnormal beta-cell function, primarily in tissues not dependent on insulin for glucose transport into the cell.
We note that the same pathophysiologic mechanisms that damage the beta-cell are also involved with (help define) the risk of developing the complications of diabetes.
The specific risk of developing complications even with similar degrees of hyperglycemia depend on genetic susceptibility to damage by the abnormal metabolic environment, , exogenous environmental factors, immune/ inflammatory factors and insulin resistance and the metabolic syndrome genetically susceptible beta cells are damaged by environmental, inflammatory/immune mechanisms and IR /dysmetabolic syndrome factors. The resultant abnormal metabolic environment resulting from abnormal fuel excess (glucose, FFAs) can iteratively exacerbate beta cell dysfunction and damage genetically susceptible peripheral cells and tissues resulting in diabetic chronic complications. The presence or absence, or degree of damage is defined by the presence or absence of the same processes (environmental, inflammatory/immune mechanisms and IR /dysmetabolic syndrome factors) that are involved in beta cell dysfunction.
The The Fuel Excess resultant from abnormal b-cell function iteratively further exacerbate b-cell dysfunction. The pathways organized by Brownlee, acting through miRNAs, oxidative stress, Barabra Corkey’s metaboloic REDOX regulators as well as epigenetics further exacerbate IR, inflammation and immune dysfunction and ,potentially, susceptibility to environmental factors
Glucotoxicity /
lipotoxicity
Cause or permit susceptibility to damage
Explains why some newer meds for DM
decrease adverse outcomes without major drops in HgA1c

10. CV Benefits of DM Meds Driven By Other Mechanisms!!
study
HgA1c
drop
eye
nerve
kidney
MACE CV
Mort MI
CVA
CHF
All
Cause
Inferences on Value of Glycemic Control and Other Mechanisms of DM meds in Reducing Complications of Diabetes
UKPDS
0.9 
Glycemic Hypothesis Proven in Primary
DCCT
~2.0
Prevention despite ‘wrong meds’
VADT
1.5 −
Glycemic Benefit could not be proven in face of
ADV.
0.8
Metabolic memory
ACCORD
1.1 
Wrong drugs, wrong process of care
BROMO-QR
(pts <7)
Benefits primarily driven
EMPA-Reg
~0.5
By other mechanisms
IRIS
IR /pre-DM
Besides glycemia, eg:
LEADER
0.4
 IR, Arterial Stiffness, Inflam.,Symp. Tone
Glycemic Hypothesis Proven in Primary Prevention in both ‘T1DM, T2DM’; Success despite ‘wrong meds’
In Older patients with T2DM- longer duration DM, and many with prexisting complications; Achieved modest ‘microvascular benefit, no CV benefit, but increased mortality in ACCORD- likely due to ‘metabolic memory, and use of ‘wrong meds’ to point of excess hypoglycemia and undue weight gain
But 4 agents recently shown to have reduction in complications-- likely due to
benefits primarily driven by other mechanisms besides glycemia, eg:  IR, Arterial Stiffness, reduced Inflammation,  Sympathetic Tone
Primary prevention
Secondary Prevention
Secondary Prevention- Drug trials with CV Benefit