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Insulin Resistance and Type 2 Diabetes

April 2012
Diabetes 61(4):778-9

DOI:10.2337/db12-0073

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PubMed

License
CC BY-NC-ND 3.0

Authors:

Taylor Roy

Newcastle University

For well over half a century, the link between insulin resistance and type 2 diabetes has been recognized. Insulin resistance is important. Not only is it the most powerful predictor of future development of type 2 diabetes, it is also a therapeutic target once hyperglycemia is present. In this issue of Diabetes , Morino et al. (1) report a series of studies that provide evidence of a genetic mechanism linking expression of lipoprotein lipase (LPL) to peroxisome proliferator–activated receptor (PPAR)-δ expression and mitochondrial function. This is likely to contribute to the muscle insulin resistance that predisposes to type 2 diabetes. Observation of abnormal mitochondrial function in vitro in type 2 diabetes (2) was soon followed by in vivo demonstration of this abnormality in insulin-resistant, first-degree relatives of people with type 2 diabetes (3). Further reports of a modest defect in muscle mitochondrial function in type 2 diabetes were published shortly thereafter (4,5). These studies raised the question of whether type 2 diabetes could be a primary disorder of the mitochondria. However, the study of first-degree relatives tended to be misinterpreted as having shown a major defect in mitochondrial function in type 2 diabetes, although it had studied nondiabetic groups from the opposite ends of the insulin resistance–sensitivity spectrum. Indeed, other studies showed no defect in mitochondrial function in type 2 diabetes (6,7), which led to further confusion. Mitochondrial function was then shown to be acutely modifiable by changing fatty acid availability (8) and that it …

Distribution curves of insulin sensitivity as measured by the euglycemic-hyperinsulinemic clamp showing that people with type 2 diabetes sit within the range of the nondiabetic distribution, but toward the lower range. Identification of factors underlying muscle insulin resistance itself can be investigated by comparing groups drawn from the extremes of the total population distribution. Such factors may not be clearly discernible when type 2 diabetic individuals are compared with normoglycemic control subjects matched for weight and physical activity. The data are from previously published population studies of normal glucose tolerance (n = 256), impaired glucose tolerance (n = 119), and type 2 diabetes (n = 194) (20,21).

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Insulin Resistance and Type 2 Diabetes

Roy Taylor

or well over half a century, the link between in-

sulin resistance and type 2 diabetes has been

recognized. Insulin resistance is important. Not

only is it the most powerful predictor of future

development of type 2 diabetes, it is also a therapeutic

target once hypergly cemia is present. In this issue of

Diabetes, Morino et al. (1) report a series of studies that

provide evidence of a genetic mechanism linking expres-

sion of lipoprotein lipase (LPL) to peroxisome proliferator–

activated receptor (PPAR)-d expression and mitochondrial

function. This is likely to contribute to the muscle insulin

resistance that predisposes to type 2 diabetes.

Observation of abnormal mitochondrial function in vitro

in type 2 diabetes (2) was soon followed by in vivo dem-

onstration of this abnormality in insulin-resistant, ﬁrst-

degree relatives of people with type 2 diabetes (3). Further

reports of a modest defect in muscle mitochondrial function

in type 2 diabetes were published shortly thereafter (4,5).

These studies raised the question of whether type 2 diabetes

could be a primary disorder of the mitochondria. However,

the study of ﬁrst-degree relatives tended to be misinter-

preted as having shown a major defect i n mitochondrial

function in type 2 diabetes, although it had studied non-

diabetic groups from the opposi te ends of the insulin

resistance–sensitivi ty spectrum. Indeed, other studies showed

no defect in mitochondrial function in type 2 diabetes

(6,7), which led to further confusion. Mitochondrial func-

tion was then shown to be acutely modiﬁable by changing

fatty acid availability (8) and that it was affected by am-

bient blood glucose concentration (9). When ambient

blood glucose levels were near normal in diabetes, no de-

fect in mitochondrial function was apparent.

But if mitochondrial function in well-controlled type 2 di-

abetes is not abnormal, is a defect in insulin-resistant, ﬁrst-

degree relatives clinically relevant? The answer is provided in

Fig. 1, which shows population distributions of insulin sen-

sitivity for normoglycemia, impaired glucose tolerance, and

type 2 diabetes. The wide range of insulin sensitivity in the

normoglycemic population fully encompasses the range ob-

served in type 2 diabetes. Even though mean insulin sensi-

tivity in diabetes is lower than that of matched control

subjects, values are drawn from the same distribution and,

with matching for body weight and physical activity, differ-

ences will be relatively small. Differences in insulin sensi-

tivity will be particularly evident when making comparisons

between groups selected from the extreme ends of the

population distribution (Fig. 1). When parameters directly

linked to muscle insulin resistance are compared between

groups selected in this way, any linked difference will be

maximized, making this strategy entirely appropriate to in-

vestigate the pathophysiology of muscle insulin resistance.

Muscle insulin resistance as determined by the euglycemic-

hyperinsulinemic clamp is clearly a risk factor for develop-

ment of type 2 diabetes (10). However, the pathophysiology

of hy perglycemia in established diabetes relates to hepatic

not muscle insulin resistance. This distinction has been

elegantly demonstrated in studies of moderate calorie

restriction in type 2 diabetes, which resulted in a fall in

liver fat, normalization of hepatic insulin sensitivity, and

fasting plasma glucose, but no change in muscle insulin

resistance (11). More recent work employing severe calorie

restriction conﬁrmed previous ﬁndings and also demon-

strated a longer-term return of normal i nsulin secretion as

intrapancreatic fat content fell (12). The fact that fasting

and postprandial normoglycemia can be restored in type 2

diabetes without change in muscle insulin resistance should

not be surprising. Mice totally lacking in skeletal muscle

insulin receptors do not develop diabetes (13). People with

inactive muscle glycogen synthase are not necessarily hy-

perglycemic (14), and many normoglycemic indivi duals

maintain normal blood glucose with a degree of muscle in-

sulin resistance identical to that among people who develop

type 2 diabetes (Fig. 1). The relevance of muscle insulin re-

sistance for development of type 2 diabetes is more subtle.

er many years and only in the presence of chronic calorie

excess, hyperinsulinemia steadily brings about hepatic fat

accumulation and hepatic insulin resistance. Onset of hy-

perglycemia is ultimately determined by failure of nutrient-

stimulated insulin secretion (15). This new understanding is

described by the twin cycle hypothesis (16). So what actually

determines this critical primary insulin resist ance in muscle?

Morino et al. (1) report analyses of mRNA in muscle

biopsies to compare expression of genes involved in mi-

tochondrial fatty acid oxidation. Their experiments com-

pare data for subjects at opposite extremes of the insulin

resistance spectrum. Findings were conﬁrmed in indepen-

dent groups selected in the same way and two genes were

found to be consistently lower in expression. Using knock

down of expression by appropriate inhibitory RNA, Western

blotting showed that LPL was the important gene product.

In both human rhabdomyosarcoma cells and L6 myocytes,

such knock down of LPL induced a decrease in mitochon-

drial density. The function of LPL is to release fatty acids

from triglyceride for direct cellular uptake. The biological

relevance of the link between decreased mitochondrial

numbers and RNA interference (RNAi) inhibition of LPL

was conﬁ rmed by observing that the effect was only seen

if fat was present in the extracellular media. To test

the hypothesis that fatty acid ﬂux into cells regulates

mitochondrial biogenesis by a PPAR-dependent process,

knock down of PPAR-d was also shown to decrease mi-

tochondrial density. Furthermore, limitation of fatty acid

uptake by directly inhibiting the transmembrane fatty

From the Magnetic Reso nance Cent re, Campus for Age ing and Vitali ty,

Newcastle University, Newcastle upon Tyne, U.K.

Corresponding author: Roy Taylor, roy.taylor@ncl.ac.uk.

DOI: 10.2337/db12-0073

Ó 2012 by the American Diabetes Association. Readers may use this article as

long as the work is properly cited, the use is educational and not for proﬁt,

and the work is not altered. See http://creativecommons.org/licenses/by

-nc-nd/3.0/ for details.

See accompanying original article, p. 877.

778 DIABETES, VOL. 61, APRIL 2012 diabetes.diabetesjournals.org

COMMENTARY

transporter CD36 was shown to achieve the same effect.

Overall, these studies suggest that insulin resistance is

related to decreased mitochondrial content in muscle due,

at least in part, to reductions in LPL e xpression and con-

sequent decreased PPAR-d activation.

This important article establishes a biological mecha-

nism whereby insulin resistance in muscle is causally linked

to genetic inﬂuences that are measurable in the general

population. It focuses on insulin resistance by comparing

extremes of the distribution of this characteristic in the

normal population. But does insulin resistance cause mito-

chondrial dysfunction, or vice versa? The former appears

more likely on the basis of current evidence. Exercise

can reduce insulin resistance and ameliorate mitochondrial

dysfunction (17), whereas established mitochondrial dys-

function does not necessarily produce insulin resistance in

animal models or in humans (18,19). Understanding the

nature of common insulin resistance in muscle and its re-

lationship to type 2 diabetes is long overdue. Future work

should determine whether speciﬁc therapeutic manipula-

tion can offset the effect of identiﬁable genetic inﬂuences

and interrupt the long run-in to type 2 diabetes.

ACKNOWLEDGMENTS

No potential conﬂicts of interest relevant to this article

were reported.

The author is grateful to Leif Groop of Lund University

for permi ssion to use combined data from the Botnia

Study and the Malmö Prospective Study in Fig. 1 and to

Jasmina Kravic of Lund University for replotting the data.

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FIG. 1. Distribution curves of insulin sensitivity as measured by the euglycemic-hyperinsulinemic clamp showing that people with type 2

diabetes s it within the range of the nondiabetic distribution, but toward the lower range. Identiﬁcation of factors underlying muscle insulin

resistance itself can be investigated by comparing groups drawn from the extremes of the total population distribution. Such factors may

not be clearly discernible when type 2 diabetic individuals are compared with normogly cemic control subjects matched for weight and

physical activity. The data are from previously published population studies of normal glucose tolerance (n = 256), impaired glucose

tolerance (n = 119), and type 2 diabetes (n = 194) (20,21).

R. TAYLOR

diabetes.diabetesjournals.org DIABETES, VOL. 61, APRIL 2012 779

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Jun 2011
DIABETOLOGIA

Type 2 diabetes is regarded as inevitably progressive, with irreversible beta cell failure. The hypothesis was tested that both beta cell failure and insulin resistance can be reversed by dietary restriction of energy intake. Eleven people with type 2 diabetes (49.5 ± 2.5 years, BMI 33.6 ± 1.2 kg/m(2), nine male and two female) were studied before and after 1, 4 and 8 weeks of a 2.5 MJ (600 kcal)/day diet. Basal hepatic glucose output, hepatic and peripheral insulin sensitivity and beta cell function were measured. Pancreas and liver triacylglycerol content was measured using three-point Dixon magnetic resonance imaging. An age-, sex- and weight-matched group of eight non-diabetic participants was studied. After 1 week of restricted energy intake, fasting plasma glucose normalised in the diabetic group (from 9.2 ± 0.4 to 5.9 ± 0.4 mmol/l; p = 0.003). Insulin suppression of hepatic glucose output improved from 43 ± 4% to 74 ± 5% (p = 0.003 vs baseline; controls 68 ± 5%). Hepatic triacylglycerol content fell from 12.8 ± 2.4% in the diabetic group to 2.9 ± 0.2% by week 8 (p = 0.003). The first-phase insulin response increased during the study period (0.19 ± 0.02 to 0.46 ± 0.07 nmol min(-1) m(-2); p < 0.001) and approached control values (0.62 ± 0.15 nmol min(-1) m(-2); p = 0.42). Maximal insulin response became supranormal at 8 weeks (1.37 ± 0.27 vs controls 1.15 ± 0.18 nmol min(-1) m(-2)). Pancreatic triacylglycerol decreased from 8.0 ± 1.6% to 6.2 ± 1.1% (p = 0.03). Normalisation of both beta cell function and hepatic insulin sensitivity in type 2 diabetes was achieved by dietary energy restriction alone. This was associated with decreased pancreatic and liver triacylglycerol stores. The abnormalities underlying type 2 diabetes are reversible by reducing dietary energy intake.

Inhibition of lipolysis in Type 2 diabetes normalizes glucose disposal without change in muscle glycogen synthesis rates

Article

Full-text available

Mar 2011
CLIN SCI

Suppression of lipolysis by acipimox is known to improve insulin-stimulated glucose disposal, and this is an important phenomenon. The mechanism has been assumed to be an enhancement of glucose storage as glycogen, but no direct measurement has tested this concept or its possible relationship to the reported impairment in insulin-stimulated muscle ATP production. Isoglycaemic-hyperinsulinaemic clamps with [13C]glucose infusion were performed on Type 2 diabetic subjects and matched controls with measurement of glycogen synthesis by 13C MRS (magnetic resonance spectroscopy) of muscle. 31P saturation transfer MRS was used to quantify muscle ATP turnover rates. Glucose disposal rates were restored to near normal in diabetic subjects after acipimox (6.2 ± 0.8 compared with 4.8 ± 0.6 mg·kgffm⁻¹·min⁻¹; P<0.01; control 6.6 ± 0.5 mg·kgffm⁻¹·min⁻¹; where ffm, is fat-free mass). The increment in muscle glycogen concentration was 2-fold higher in controls compared with the diabetic group, and acipimox administration to the diabetic group did not increase this (2.0 ± 0.8 compared with 1.9 ± 1.1 mmol/l; P<0.05; control, 4.0 ± 0.8 mmol/l). ATP turnover rates did not increase during insulin stimulation in any group, but a modest decrease in the diabetes group was prevented by lowering plasma NEFAs (non-esterified fatty acids; 8.4 ± 0.7 compared with 7.1 ± 0.5 μmol·g⁻¹·min⁻¹; P<0.05; controls 8.6 ± 0.8 μmol·g⁻¹·min⁻¹). Suppression of lipolysis increases whole-body glucose uptake with no increase in the rate of glucose storage as glycogen but with increase in whole-body glucose oxidation rate. ATP turnover rate in muscle exhibits no relationship to the acute metabolic effect of insulin.

Lower Intrinsic ADP-Stimulated Mitochondrial Respiration Underlies In Vivo Mitochondrial Dysfunction in Muscle of Male Type 2 Diabetic Patients

Article

Full-text available

Sep 2008

A lower in vivo mitochondrial function has been reported in both type 2 diabetic patients and first-degree relatives of type 2 diabetic patients. The nature of this reduction is unknown. Here, we tested the hypothesis that a lower intrinsic mitochondrial respiratory capacity may underlie lower in vivo mitochondrial function observed in diabetic patients. Ten overweight diabetic patients, 12 first-degree relatives, and 16 control subjects, all men, matched for age and BMI, participated in this study. Insulin sensitivity was measured with a hyperinsulinemic-euglycemic clamp. Ex vivo intrinsic mitochondrial respiratory capacity was determined in permeabilized skinned muscle fibers using high-resolution respirometry and normalized for mitochondrial content. In vivo mitochondrial function was determined by measuring phosphocreatine recovery half-time after exercise using (31)P-magnetic resonance spectroscopy. Insulin-stimulated glucose disposal was lower in diabetic patients compared with control subjects (11.2 +/- 2.8 vs. 28.9 +/- 3.7 micromol x kg(-1) fat-free mass x min(-1), respectively; P = 0.003), with intermediate values for first-degree relatives (22.1 +/- 3.4 micromol x kg(-1) fat-free mass x min(-1)). In vivo mitochondrial function was 25% lower in diabetic patients (P = 0.034) and 23% lower in first-degree relatives, but the latter did not reach statistical significance (P = 0.08). Interestingly, ADP-stimulated basal respiration was 35% lower in diabetic patients (P = 0.031), and fluoro-carbonyl cyanide phenylhydrazone-driven maximal mitochondrial respiratory capacity was 31% lower in diabetic patients (P = 0.05) compared with control subjects with intermediate values for first-degree relatives. A reduced basal ADP-stimulated and maximal mitochondrial respiratory capacity underlies the reduction in in vivo mitochondrial function, independent of mitochondrial content. A reduced capacity at both the level of the electron transport chain and phosphorylation system underlies this impaired mitochondrial capacity.

Insulin Resistance and Insulin Secretory Dysfunction as Precursors of Non-Insulin-Dependent Diabetes Mellitus: Prospective Studies of Pima Indians

Article

Full-text available

Jan 1994

The relative roles of obesity, insulin resistance, insulin secretory dysfunction, and excess hepatic glucose production in the development of non-insulin-dependent diabetes mellitus (NIDDM) are controversial. We conducted a prospective study to determine which of these factors predicted the development of the disease in a group of Pima Indians. A body-composition assessment, oral and intravenous glucose-tolerance tests, and a hyperinsulinemic--euglycemic clamp study were performed in 200 non-diabetic Pima Indians (87 women and 113 men; mean [+/- SD] age, 26 +/- 6 years). The subjects were followed yearly thereafter for an average of 5.3 years. Diabetes developed in 38 subjects during follow-up. Obesity, insulin resistance (independent of obesity), and low acute plasma insulin response to intravenous glucose (with the degree of obesity and insulin resistance taken into account) were predictors of NIDDM: The six-year cumulative incidence of NIDDM was 39 percent in persons with values below the median for both insulin action and acute insulin response, 27 percent in those with values below the median for insulin action but above that for acute insulin response, 13 percent in those with values above the median for insulin action and below that for acute insulin response, and 0 in those with values originally above the median for both characteristics. Insulin resistance is a major risk factor for the development of NIDDM: A low acute insulin response to glucose is an additional but weaker risk factor.

Impaired mitochondrial activity and insulin-resistant offspring of patients with type 2 diabetes - Reply

Article

Jun 2004

Total Skeletal Muscle PGC-1 Deficiency Uncouples Mitochondrial Derangements from Fiber Type Determination and Insulin Sensitivity

Article

Dec 2010

Evidence is emerging that the PGC-1 coactivators serve a critical role in skeletal muscle metabolism, function, and disease. Mice with total PGC-1 deficiency in skeletal muscle (PGC-1α(-/-)β(f/f/MLC-Cre) mice) were generated and characterized. PGC-1α(-/-)β(f/f/MLC-Cre) mice exhibit a dramatic reduction in exercise performance compared to single PGC-1α- or PGC-1β-deficient mice and wild-type controls. The exercise phenotype of the PGC-1α(-/-)β(f/f/MLC-Cre) mice was associated with a marked diminution in muscle oxidative capacity, together with rapid depletion of muscle glycogen stores. In addition, the PGC-1α/β-deficient muscle exhibited mitochondrial structural derangements consistent with fusion/fission and biogenic defects. Surprisingly, the proportion of oxidative muscle fiber types (I, IIa) was not reduced in the PGC-1α(-/-)β(f/f/MLC-Cre) mice. Moreover, insulin sensitivity and glucose tolerance were not altered in the PGC-1α(-/-)β(f/f/MLC-Cre) mice. Taken together, we conclude that PGC-1 coactivators are necessary for the oxidative and mitochondrial programs of skeletal muscle but are dispensable for fundamental fiber type determination and insulin sensitivity.

Deficiency of electron transport chain in human skeletal muscle mitochondria in type 2 diabetes mellitus and obesity

Article

Nov 2009
AM J PHYSIOL-ENDOC M

Insulin resistance in skeletal muscle in obesity and T2DM is associated with reduced muscle oxidative capacity, reduced expression in nuclear genes responsible for oxidative metabolism, and reduced activity of mitochondrial electron transport chain. The presented study was undertaken to analyze mitochondrial content and mitochondrial enzyme profile in skeletal muscle of sedentary lean individuals and to compare that with our previous data on obese or obese T2DM group. Frozen skeletal muscle biopsies obtained from lean volunteers were used to estimate cardiolipin content, mtDNA (markers of mitochondrial mass), NADH oxidase activity of mitochondrial electron transport chain (ETC), and activity of citrate synthase and beta-hydroxyacyl-CoA dehydrogenase (beta-HAD), key enzymes of TCA cycle and beta-oxidation pathway, respectively. Frozen biopsies collected from obese or T2DM individuals in our previous studies were used to estimate activity of beta-HAD. The obtained data were complemented by data from our previous studies and statistically analyzed to compare mitochondrial content and mitochondrial enzyme profile in lean, obese, or T2DM cohort. The total activity of NADH oxidase was reduced significantly in obese or T2DM subjects. The cardiolipin content for lean or obese group was similar, and although for T2DM group cardiolipin showed a tendency to decline, it was statistically insignificant. The total activity of citrate synthase for lean and T2DM group was similar; however, it was increased significantly in the obese group. Activity of beta-HAD and mtDNA content was similar for all three groups. We conclude that the total activity of NADH oxidase in biopsy for lean group is significantly higher than corresponding activity for obese or T2DM cohort. The specific activity of NADH oxidase (per mg cardiolipin) and NADH oxidase/citrate synthase and NADH oxidase/beta-HAD ratios are reduced two- to threefold in both T2DM and obesity.

Pathogenesis of Type 2 diabetes: Tracing the reverse route from cure to cause

Article

Nov 2008

Taylor Roy

The metabolic abnormalities of type 2 diabetes can be reversed reproducibly by bariatric surgery. By quantifying the major pathophysiological abnormalities in insulin secretion and insulin action after surgery, the sequence of events leading to restoration of normal metabolism can be defined. Liver fat levels fall within days and normal hepatic insulin sensitivity is restored. Simultaneously, plasma glucose levels return towards normal. Insulin sensitivity of muscle remains abnormal, at least over the weeks and months after bariatric surgery. The effect of the surgery is explicable solely in terms of energy restriction. By combining this information with prospective observation of the changes immediately preceding the onset of type 2 diabetes, a clear picture emerges. Insulin resistance in muscle, caused by inherited and environmental factors, facilitates the development of fatty liver during positive energy balance. Once established, the increased insulin secretion required to maintain plasma glucose levels will further increase liver fat deposition. Fatty liver causes resistance to insulin suppression of hepatic glucose output as well as raised plasma triacylglycerol. Exposure of beta cells to increased levels of fatty acids, derived from circulating and locally deposited triacylglycerol, suppresses glucose-mediated insulin secretion. This is reversible initially, but eventually becomes permanent. The essential time sequence of the pathogenesis of type 2 diabetes is now evident. Muscle insulin resistance determines the rate at which fatty liver progresses, and ectopic fat deposition in liver and islet underlies the related dynamic defects of hepatic insulin resistance and beta cell dysfunction. These defects are capable of dramatic reversal under hypoenergetic feeding conditions, completely in early diabetes and to a worthwhile extent in more established disease.

Insulin Resistance and Type 2 Diabetes

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