Professional Documents
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673
Christopher J. Nolan,1 Neil B. Ruderman,2 Steven E. Kahn,3 Oluf Pedersen,4 and Marc Prentki5
Insulin Resistance as a
Physiological Defense Against
Metabolic Stress: Implications
for the Management of Subsets
of Type 2 Diabetes
Diabetes 2015;64:673686 | DOI: 10.2337/db14-0694
PERSPECTIVES IN DIABETES
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Figure 1Hypothetical model illustrating the molecular basis of insulin-induced metabolic stress in patients with poorly controlled T2D in
which both blood glucose and FFA levels are persistently elevated. Depicted here is a cell in which (A) IR protects from nutrient overload
and metabolic stress by limiting glucose ux into the cell and (B) the IR protection is overridden by a high dose of exogenous insulin
therapy, which promotes excess glucose uptake and glucolipotoxicity. Excess glucose supply to the mitochondria results in reducing
equivalent overload of the electron transfer chain and enhanced production of ATP and ROS, resulting in oxidative damage. The resulting
increased ATP/AMP ratio inhibits AMPK, which has the effect of decreasing FFA oxidation (limiting nutrient detoxication) favoring fat
deposition. Enhanced glucose uptake can also result in excessive glycogen deposition and increased activities of the toxic polyol, hexosamine, and AGE formation pathways. Glucose that is metabolized via the anaplerosis pathway can also increase cytosolic acetyl-CoA
(AcCoA) and malonyl-CoA (MalCoA). AcCoA and MalCoA are then available for cholesterol and fatty acid synthesis, increasing the lipid load
on the cell. MalCoA also inhibits fatty acyl-CoA (FACoA) entry into the mitochondria such that FACoA is more available for synthesis of
complex lipids, including glycerolipids (phospholipids, diacylglycerols, and triglycerides) and ceramides. This can result in endoplasmic
reticulum stress and the accumulation of lipid droplets (steatosis). Increased ROS production, toxic lipid accumulation, and reduced AMPK
activity are factors that also activate the inammasome contributing to cardiac injury. The overall effect is nutrient overload and metabolic
stress causing cell dysfunction or death and cardiac inammation. CD36, free fatty acid transporter; DAG, diacylglycerols; ER, endoplasmic
reticulum; ETC, electron transport chain; GLUT4, facilitative glucose transporter 4; IRc, insulin receptor; MITO DYSF, mitochondrial
dysfunction; OXID STRESS, oxidative stress; Pyr, pyruvate; PL, phospholipids; TG, triglycerides; Tx, treatment.
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Figure 2Differential benecial or adverse effects of insulin therapy on vascular endothelial cells depending on the level of metabolic
control achieved. Insulin signaling in endothelial cells can be via the PI3K (causes vasodilation and is anti-thrombotic) and the MAPK
pathway (causes vasoconstriction and is prothrombotic) such that there is a balance of benecial and harmful effects. In response to an
excess nutrient supply, as occurs in metabolically uncontrolled T2D, selective IR in the PI3K pathway will occur such that signaling through
the MAPK pathway will be unopposed, increasing the risk of vascular events. Insulin treatment will either improve or worsen vascular health
depending on whether it is effective or not at bringing blood nutrient levels under control. If high exogenous insulin therapy is successful at
improving blood nutrient levels, then insulin signaling through the PI3K pathway will increase such that insulin therapy will be benecial to
blood vessel health. However, if high dose exogenous insulin therapy fails to control blood nutrients (i.e., in refractory patients), then the IR
in the PI3K pathway will not be relieved and insulin signaling will predominate via the harmful MAPK pathway and increase the risk of
vascular events.
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Table 1Major trials of intensive vs. conventional glucose lowering in subjects with T2D
Subjects (n)
UKPDS-33
(Int-SU or Insulin)
UKPDS-34
(Int-Metformin)
ADVANCE
ACCORD
VADT
3,867
753a
11,140
10,251
1,794
Baseline characteristics
Age (years)
BMI (kg/m2)
Diabetes duration (years)
Cardiovascular disease
history (%)
HbA1c (%)
53
28
0
53
32
0
66
28
8
62
32
10
60
31
11.5
NR
7.1
NR
7.2
32
7.5
35
8.3
40
9.4
10.0
10.7
5.0
3.5
5.6
6 vs. 2.5
1 vs. 1
NR
NR
0.94 [0.841.06]
0.90 [0.781.04]
0.88 [0.741.05]
0.79 [0.581.09]
0.69 [0.351.64]
0.98 [0.781.23]
0.76 [0.620.92]
NR
0.84 [0.711.00]
0.61 [0.410.89]
NR
NR
0.82 [0.591.14]
0.85 [0.740.97]d
0.67 [0.510.89]d
1.02 [0.661.57]
NR
0.88 [0.741.04]
1.35 [1.041.76]
1.32 [0.812.14]
0.94 [0.81.1]
0.64 [0.450.91]
0.93 [0.831.06]
1.22 [1.011.46]
1.07 [0.811.42]
0.87 [0.790.96]d
0.73 [0.590.92]d
Younger, leaner,
recent-onset
diabetes. Less
aggressive
glycemic
control and
moderate weight
gain in Int group.
Younger, obese,
recent-onset
diabetes. Less
aggressive
glycemic
control and low
weight gain in
Int group.
Older, leaner,
long duration
of diabetes.
High use of SU
and low use
of insulin and
TZD. No weight
gain in Int group.
Older, more
obese, long
duration of
diabetes.
High use of
insulin and
TZD and high
weight gain in
Int group.
Older, obese,
long duration
of diabetes.
High use
of insulin
and high
weight gain
in Int group.
Results
Duration of follow-up (years)
HbA1c achieved, Int vs.
Conv (%)
Change in weight to study
end (kg)
Change in weight, Int vs.
Conv (kg/year of follow-up)
Primary cardiovascular outcome
(HR or RR [95% CI])
Myocardial infarct (nonfatal)
(HR or RR [95% CI])
Myocardial infarct (all)
(HR or RR [95% CI])
Myocardial infarct (extended
follow-up) (RR [95% CI])
Cardiovascular death
(HR or RR [95% CI])
All-cause mortality
(HR or RR [95% CI])
All-cause mortality (extended
follow-up) (RR [95% CI])
Comments
UKPDS (4648), ADVANCE (50), ACCORD (42), VADT (49). Conv, conventional treatment; RR, risk ratio; Int, intensive treatment; NR, not
recorded; SU, sulfonylurea. ACCORD and VADT had intensive glucose lowering involving intensive insulin use and were associated with
weight gain greater than 1.0 kg/year. Bold typeface indicates signicant changes. aMetformin-based intensively treated vs. conventionally
treated subjects only. bGlucose-lowering therapy at last recorded study visit. cMeasured at 3 years. dUKPDS 10-year post-trial follow-up.
which components of the approach contributed to the improved outcome. Of relevance here, the glucose-lowering
component in the intervention group was not that intensive, as the HbA1c at the end of the intervention period had
only come down from 8.4 to 7.9% and weight gain was
negligible in men (BMI increase of 0.7 kg/m2 in 7.8 years)
and moderate in women (BMI increase of 2.3 kg/m2) (52).
A meta-analysis of UKPDS, ADVANCE, ACCORD, and
VADT showed that intensive versus standard glycemic
approaches were associated with a small reduction in
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Table 2Major clinical trials of insulin treatment vs. conventional glucose lowering in subjects with T2D (ACCORD study also
shown)
Subjects (n)
ACCORD
DIGAMI 1
DIGAMI 2
BARI 2D
ORIGIN
10,251
620
780a
1,944b
12,537c
62
32
10
68
27
10
68
28
8.3
62
32
10.4
64
30
05.4
35
8.1
100
8.1
100
7.2
100
7.7
59
6.4
Insulin vs.
Conv
72 vs. 49d
NR
NR
NR
Insulin vs.
Conv
85 vs. 39f
6 vs. 22f
7 vs. 33f
Insulin vs.
insulin sensitivity
61 vs. 29i
75 vs. 11i
52 vs. 18i
4 vs. 62i
Insulin vs.
Conv
80 vs. 11g
47 vs. 60g
25 vs. 47g
NR
3.5
1.0
2.1
5.3
6.2
NR
NR
0.90 [0.781.04]
NR
1.22 [0.951.56]
1.03 [0.981.08]j
1.02 [0.941.11]
0.76 [0.620.92]
1.30 [0.832.04]d
NR
NR
1.02 [0.941.11]
NR
0.99 [0.701.39]d
1.36 [0.912.03]
1.02 [0.881.19]
1.35 [1.041.76]
0.72 [0.530.98]d
NR
NR
1.00 [0.891.13]
1.22 [1.011.46]
0.71 [0.490.96]d
1.26 [0.921.72]
1.00 [0.971.03]
0.98 [0.901.08]
0.72 [0.550.92]e
1.17 [0.901.52]h
Less obese
group. Less
intensive glucose
lowering in Ins
group. Weight
gain not
recorded.
Less obese
group. High
weight gain
in Ins group.
Obese group.
Less intense
glucose lowering
in Ins group.
Obese group.
Short duration
of diabetes,
lower HbA1c
at baseline.
Low weight
gain in
Ins group.
Baseline characteristics
Age (years)
BMI (kg/m2)
Diabetes duration (years)
Cardiovascular disease
history (%)
HbA1c (%)
Glucose-lowering therapy use
Insulin (%)
Metformin (%)
Sulfonylurea (%)
TZD (%)
Results
Duration of follow-up (years)
HbA1c achieved, Insulin
(or Int) vs. Conv (%)
Change in weight, Insulin
(or Int) vs. Conv (kg)
Change in weight, Insulin
(or Int) vs. Conv (kg/year
of follow-up)
Primary cardiovascular
(HR or RR [95% CI])
Myocardial infarct (nonfatal)
(HR or RR [95% CI])
Myocardial infarct (all)
(HR or RR [95% CI])
Cardiovascular death
(HR or RR [95% CI])
All-cause mortality
(HR or RR [95% CI])
All-cause mortality (extended
follow-up) (HR [95% CI])
Comments
77
95
78
92
vs.
vs.
vs.
vs.
55
87
68
58
Obese group.
Aggressive glucose
lowering with
high insulin
and TZD use
and high weight
gain in Int group.
ACCORD (42), DIGAMI 1 and 2 (5557), BARI 2D (58), ORIGIN (60). Conv, conventional treatment; Ins, insulin treatment; Int, intensive
treatment; RR, risk ratio of insulin (or intensive therapy) vs. comparator therapy; NR, not recorded. ACCORD and DIGAMI 2 studies had
intensive glucose lowering involving intensive insulin use and were associated with weight gain greater than 1.0 kg/year. Bold typeface
indicates signicant changes. aComparison of group 1 (acute insulinglucose infusion for 24 h followed by insulin-based long-term
glucose control) vs. group 3 (routine metabolic management). bInsulin provision vs. insulin sensitization groups. cInsulin glargine vs.
standard care. At d12-month and e3.4-year time points. fAt initial discharge from hospital. gAt study end. hDIGAMI 2 follow-up. iAt 3
years of follow-up. jPrimary cardiovascular in revascularization subgroup (HR 1.24, P = 0.059).
example, the paradox could be explained if intensively treated patients achieving better glycemic control have reduced
myocardial infarcts and those patients with ongoing poor
control have more fatal events. If not a consequence of worsening atherosclerosis, then alternative mechanisms need to
be considered. One alternative mechanism, as discussed
earlier in this Perspective, could be a detrimental effect of
intensive glycemic treatment causing insulin-induced metabolic stress in the heart in some individuals (a metabolic
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Table 3Other major cardiovascular outcome studies in T2D (ACCORD study also shown)
Subjects (n)
ACCORD
Look AHEAD
EXAMINE
SAVOR-TIMI 53
10,251
5,145
5,380
16,492
62
32
10
35
8.1
59
36
5
14
7.2
61
29
7
100
8.0
65
31
10
79
8.0
Int lifestyle
vs. Conv
33 vs. 40b
67 vs. 67b
NR
NR
Alogliptin vs.
placebo
29 vs. 30e
65 vs. 67e
47 vs. 46e
2.4 vs. 2.5e
Saxagliptin vs.
placebo
43 vs. 46g
70 vs. 70g
39 vs. 40g
4.7 vs. 4.7g
9.6
Diff 20.22 Int
vs. Convc
Diff 24 Int
vs. Convc
1.5
7.7 vs. 8.1f
2.1
7.5 vs. 7.8g
0.90 [0.781.04]
0.95 [0.831.09]
0.96 [# 1.16]
1.00 [0.891.12]
0.76 [0.620.92]
0.86 [0.691.06]
1.08 [0.881.33]
NR
0.44 [0.151.26]
NR
NR
0.84 [0.681.04]
0.80 [0.611.04]d
0.88 [0.621.29]
0.85 [0.691.04]
NR
NR
0.79 [0.601.04]
0.88 [0.711.09]
0.95 [0.81.12]
1.27 [1.071.51]
1.03 [0.871.22]
1.11 [0.961.27]
Obese group.
Aggressive glucose
lowering with
high insulin and
TZD use and high
weight gain
in Int group.
Obese group.
Weight loss
greater with
lifestyle intervention.
Not a study of
intensive glucose
lowering.
High-risk subjects.
Not a study of
intensive glucose
lowering, but
saxagliptin group
had lower HbA1c.
Moderate use
of insulin.
Baseline characteristics
Age (years)
BMI (kg/m2)
Diabetes duration (years)
Cardiovascular disease history (%)
HbA1c (%)
Glucose-lowering therapy use
Insulin (%)
Metformin (%)
Sulfonylurea (%)
TZD (%)
Results
Duration of follow-up (years)
HbA1c achieved (%)
Change in weight (kg)
Change in weight, Int or DPP-4
inhibitor vs. Conv or placebo
(kg/year of follow-up)
Primary cardiovascular
(HR [95% CI])
Myocardial infarct (nonfatal)
(HR [95% CI])
Myocardial infarct (fatal)
(Event rate or HR [95% CI])
Myocardial infarct (all)
(Event rate or HR [95% CI])
Heart failure (HR [95% CI])
Cardiovascular death (HR [95% CI])
All-cause mortality (HR [95% CI])
Comments
77
95
78
92
vs.
vs.
vs.
vs.
55
87
68
58
3.5
6.4 vs. 7.5
3.5 vs. 0.4
ACCORD (42), Look AHEAD (64), EXAMINE (73), SAVOR-TIMI 53 (72). Conv, conventional treatment; Int, intensive treatment (glucose
lowering in ACCORD; lifestyle in Look AHEAD); NR, not recorded. Bold typeface indicates signicant changes. aFatal and nonfatal heart
failure. bAt end of study. cOver course of study. dHospitalization for heart failure. eAt baseline. fAt end of study. gAt 2 years.
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and how many in VADT had difculty in achieving glycemic control and how many in the Look AHEAD study
failed to lose weight (54,64).
Overall, we believe the Look AHEAD results are more in
support of than against our premise. Clearly, the lifestyle
intervention did not have a detrimental effect on all-cause
mortality as occurred with the intensive glucose-lowering
approach used in ACCORD. It is also important to point
out that the intensive lifestyle intervention in the Look
AHEAD study was associated with an array of noncardiovascular event health benets, including improved glucose
control, blood pressure, and overall lipid control, all with
the use of fewer medications. Further, participants in the
intensive lifestyle arm reported improved quality of life,
mobility, and sleep as examples of additional benets.
CLINICAL IMPLICATIONS OF THE CONCEPTS OF
IR AS AN ADAPTIVE DEFENSE AND INSULININDUCED METABOLIC STRESS
low-dose insulin
DPP-4 inhibitors ?
Figure 3The potential benet of nutrient off-loading approaches compared with the overriding of IR to lower blood glucose in subjects
with poorly controlled T2D. Insulin-responsive tissues, such as the heart, skeletal muscle, adipose tissue, and the liver, are able to protect
themselves from nutrient-induced damage by developing IR. Other tissues, such as nerves, eye, kidney, and the vasculature, are less
protected by IR. The clinician has the choice to 1) treat the hyperglycemia with enough insulin to override IR and reduce nutrient toxicity in
tissues at longer-term risk of microvascular complications but with the risk of increasing insulin-induced metabolic stress in the insulinresponsive tissues or to 2) use alternative nutrient off-loading approaches to glucose lowering to benet all tissues. Insulin-induced
metabolic stress is more likely to occur with high-dose insulin therapy in patients who are refractory to improved glycemic regulation.
Sulfonylureas could potentially have similar effects to high-dose insulin as they increase insulin levels without effect to nutrient off-load.
Bariatric surgery, GLP-1 receptor (GLP-1R) agonists, a-glucosidase inhibitors, and SGLT2 inhibitors have well-known mechanisms by
which they nutrient off-load. Metformin likely detoxies nutrients because it is a mild inhibitor of mitochondrial function that is thought to
activate AMPK in liver and other tissues. TZDs, via promoting nutrient partitioning to adipose tissue, may nutrient off-load other more
critical tissues. DPP-4 inhibitors do not appear to have nutrient off-loading effects.
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