INSULIN RESISTANCE

CLINICAL SCENE

Metabolic syndrome : (Reavens syndrome)

Hyperinsulinaemia
Type 2 diabetes or glucose intolerance
Hypertension
Hypertriglyceridemia
Low HDL

Later additions to the syndrome:

Central obesity
Impaired fibrinolysis
Pro coagulant
Hyperuricaemia
Microalbuminuria

WHO and ATP III have slightly different definitions for the Metabolic syndrome,
but it seems like the WHO criteria may identify a greater number of obese
adults at risk for CVD. International Journal of Obesity (2005) 29, 668-674 To
make definition and screening of patients with the Metabolic syndrome easier,
the International Diabetes Federation has come up with a slight variation,
including the fasting blood sugar as a satisfactory measure (thus incorporating
the ATP III recommendations) Download the latest definition of Metabolic
syndrome (IDF consensus statement. PDF format)

The importance of identifying and defining the metabolic syndrome is partly

due to the fact that the total cardiovascular risk attributable to the syndrome
seems to exceed the sum of the risk from each of the separate components.
Diabet Med. 2004 Jan;21(1):52-8. Studies have demonstrated that the
prevalence of the metabolic syndrome is associated with worse glycaemia,
increasing albuminuria and worsening creatinine clearance even in type I
patients. Diabetes Care. 2005 Aug;28(8):2019-24.

THE BIOCHEMICAL SCENE

It is important to recognize that insulin resistance though loosely used, should

be distinguished as insulin resistance in the context of carbohydrate
metabolism (inability to stimulate muscle glucose uptake or inability to suppress
hepatic glucose production) and insulin resistance in the context of lipid
metabolism (inability to suppress lipolysis or inability to facilitate lipogenesis).
Also note that insulin-resistance can occur to the actions of insulin on the
vascular wall (normally insulin produces nitric oxide-mediated vasodilatation of
the peripheral vessels) Am J Physiol. 1994 Aug;267(2 Pt 1):E187-202 as well
as at the hypothalamic level (normally insulin increases sympathetic tone
through central actions on the hypothalamus with satiety inducing properties),
and to its action on platelets (normally insulin has anti-platelet aggregatory
effect). In this context, it has to be mentioned that insulin-resistance does not
happen with regard to its hypokalaemic and anti-natriuretic actions,
Diabetologia. 1991 Apr;34(4):275-81. as well as its actions on the ovary where it
stimulates LH production as in the polycystic ovarian syndrome.

Insulin sensitivity is inversely related to BMI above a critical threshold of

approximately 120% for ideal body weight. Insulin resistance is common, and is
present in almost all obese patients. J Clin Invest. 1980 Jun;65(6):1272-84.
Despite this only a small proportion of obese patients end up becoming
diabetic, and in fact only a third of patients with impaired glucose tolerance
ever progress to type 2 diabetes. This progression is very likely determined by
a (?) genetic predisposition to beta cell exhaustion and failure Diabetes Care.
1992 Mar;15(3):318-68. secondary to prolonged insulin resistance. Beta cell
"failure" implies multiple defects including a reduction in beta cell mass, a
decreased secretory ability of the beta cells secondary to decreased sensitivity
and response of the beta cells to usual secretagogues (as glucose) and incretins
(GLP-1 and GIP). Lipotoxicity, Diabetes. 1995 Aug;44(8):863-70. glucotoxicity
Endocr Rev. 1992 Aug;13(3):415-31, IAPP (islet associated poly peptide-
amylin) Diabetes. 1999 Feb;48(2):241-53. and adipokines (cytokines from
visceral fat) have all been implicated in the production of these defects although
their individual roles in the initiation vs. perpetuation of glucose intolerance
and subsequent onset of diabetes in various subgroups of patients is still far
from clear.

It is also not yet clear as to whether insulin resistance or insulin secretory

defect is the primary pathology (first to arise) in the development of type 2
diabetes, and which one has a stronger genetic component. Their quantitative
contribution to the pathology of type 2 diabetes is also not clear from present
studies and probably will never be established, as type 2 diabetes seems to be a
heterogeneous condition with different subsets showing variable contributions
from either of these pathologies depending on genetic and environmental
differences. The manifestations of the metabolic syndrome also vary between
patients again determined by different factors. Each of the factors may have
multiple mechanisms, with hypertension being produced in some through
intracellular calcium related mechanisms, while the renal sodium retention
might contribute in others.

SITES OF INSULIN RESISTANCE

Liver Muscle Pancreas Adipocyte Vascular

The SYSTEMIC scene

Fasting Eur J Clin Invest. 2000 Jan;30(1):45-52. and postprandial

Metabolism. 1992 Mar;41(3):264-72. plasma free fatty acid levels are higher in
patients with obesity and insulin resistance syndrome. In fact, epidemiological
studies seem to suggest that higher plasma FFA levels are independent
predictors of progression to type 2 diabetes. Diabetologia. 1997 Sep;40(9):1101-
6. The increased fatty acids induce apoptosis through excess nitric oxide
production. Proc Natl Acad Sci U S A. 1998 Mar 3;95(5):2498-502. Increased
lipolysis of triglyceride rich lipoproteins intravascularly as well as in the adipose
tissues, along with decreased uptake by liver, adipose tissue, and other organs
contributes to this excess FFA levels in the insulin resistant subject, such that
the FFA turn over is higher in obese individuals. Endocr Rev. 2002
Apr;23(2):201-29 A resistance to insulin's suppressive action on the hormone
sensitive lipase in adipose tissue is probable, Metabolism. 1992 Mar;41(3):264-
72 accounting for the increased lipolysis in the insulin resistant individual
although this has not been consistently borne out in all studies. Am J Physiol
263:E79E84 Augmented TNF expression seems to facilitate increased
circulating FFA through antagonism of the antilipolytic properties of insulin.
Diabetes Obes Metab. 2001 Aug;3 Suppl 1:S11-9. The alternative hypothesis is
that while hormone sensitive lipase remains sensitive to insulin action, the
increasing amount of fat mass overwhelms insulin's suppressive effect on HSL.
In keeping with this notion is that when normalized per total body fat, lipolysis
is normal or reduced in the obese. Acta Med Scand. 1969 Apr;185(4):351-6.

Abnormalities in Fatty Acid binding proteins (FABP-2) could result in increased

intestinal fat absorption resulting in higher fatty acid levels, Arterioscler Thromb
Vasc Biol. 1998 Oct;18(10):1606-10 and insulin resistance Clin Biochem.
1998 Nov;31(8):609-12 although these polymorphisms and their fat
absorptive effects is restricted to specific populations, J Clin Invest. 1995
Mar;95(3):1281-7. with inconsistencies in studies with regard to enhancement
of intestinal fat absorption. Metabolism. 2001 Apr;50(4):473-6. On a similar
note, defects or deficiency of fatty acid receptors or transporters (e.g. CD36, a
scavenger receptor) could result in defective uptake of fatty acids into adipose
tissue J Biol Chem. 2000 Oct 20;275(42):32523-9. with resultant higher
serum free fatty acid levels and induction of insulin resistance in rodents,
Lancet. 2001 Mar 3;357(9257):651-2. as well as in some human populations.
Lancet. 2001 Mar 3;357(9257):686-7, although its physiological relevance if
any, still remains unclear. Am J Physiol Endocrinol Metab. 2000
Nov;279(5):E1072-9. ASP or acyl stimulation protein is another adipocyte
derived factor that may play a role in determining fatty acid esterification
through a PKC-dependent pathway. J Biol Chem. 1999 Jun 25;274(26):18243-
51. Although increased in obesity, its physiological contribution to the
elevated FFA levels remains to be clarified. GPR40, a free fatty acid receptor on
pancreatic beta cells may function as a signalling molecule and regulate insulin
secretion Hepatol Res. 2005 Oct 5 and may be involved in the secretory
abnormalities mediated by free fatty acids that accompany insulin resistance.

The HEPATIC Connection

Normally, during an overnight fast the liver is the major contributor to plasma
glucose through glycogenolysis and gluconeogenesis. This basal hepatic glucose
production is increased in type 2 diabetics due to incomplete suppression of
endogenous glucose production by the liver. Metabolism. 1988 Jan;37(1):15-21
This is despite the fasting hyperinsulinaemia, reflecting the insulin-resistance
to carbohydrate metabolism in the liver. This increased HGP is predominantly
due to gluconeogenesis (proved by deuterated water and MRI).
So what causes this insulin resistance in the liver? Hepatic fatty infiltration has
been closely correlated to hepatic insulin resistance, independent of general
obesity. J Biol Chem. 2000 Mar 24;275(12):8456-60. Ectopic fat storage
hypothesis assumes that overwhelming of the adipocyte storage space diverts
triglycerides to the liver (and muscle) producing steatohepatitis resulting in
resistance to insulin action at this site. Ann N Y Acad Sci. 2002 Jun;967:363-
78. In this context, it is important to note that insulin is unable to suppress
hepatic glucose production in mice lacking the insulin receptor in the liver. Mol
Cell. 2000 Jul;6(1):87-97.

Resistance to insulin's actions on lipid metabolism in the liver results in a lack

of suppression of VLDL output by the liver. This excess VLDL production by the
liver is partly due to increased substrate (NEFA) delivery of to the liver from
unsuppressed lipolysis in the adipose tissue due to local insulin resistance at
that site, and partly due to a hepatic defect in suppression of VLDL production.
Diabetologia. 1997 Apr;40(4):454-62. This excess triglyceride (VLDL) production
by the liver results in increased CETP-mediated transfer of triglycerides to HDL,
thus converting HDL to HDL3. The increased transfer of triglycerides to HDL
results in its increased clearance from circulation by hepatic lipase producing
the characteristic profile in insulin resistant states. Triglyceride transfer also
occurs from VLDL to LDL, thus making LDL also more susceptible to hepatic
lipase, converting it into the smaller dense LDL particles which is atherogenic.

Interestingly people with IGT have normal HGP and normal fasting glucose
despite marked fasting hyperinsulinaemia. This is probably due to the high post
absorptive plasma insulin levels being sufficient to overcome the hepatic insulin
resistance thus maintaining the basal HGP normal. The high post absorptive
plasma insulin levels in this setting is attributed to the defective first phase
insulin response resulting in hyperglycemia which stimulates a higher than
usual second phase response of insulin secretion.

The MUSCULAR Scene

Skeletal muscle in T2 diabetes is resistant to insulin action. There is a 50%

reduction in the ability of insulin to increase muscle glucose disposal in type 2
diabetes. This muscle insulin resistance is well established in IGT individuals as
well.

Yet, muscle insulin receptors are not crucial to facilitate muscle uptake of
glucose, as hyperglycaemia itself can produce glucose uptake in muscles. In
keeping with this, rats with tissue specific deletion of the muscle insulin
receptor have normal glucose and insulin concentrations. Mol Cell. 1998
Nov;2(5):559-69. Note that the number of insulin receptors and transporters
as GLUT4 and the affinity of insulin for receptors in muscle are mostly normal
despite insulin resistance. Instead multiple intracellular signalling defects have
been identified as the cause of defective insulin action at the muscular level,
namely:

1. Defective insulin receptor tyrosine phosphorylation so that Insulin is unable

to activate the insulin receptor.
2. Defective IRS-1 (Insulin receptor substrate) phosphorylation and PI-3
(Phosphatidyl Inositol) activation by insulin.
3. Impaired ability of PI-3 to induce GLUT4 translocation.
4. Other defects as defective muscle glucose phosphorylation by hexokinase 2
are also well described in IGT and diabetes.
All these provide various areas to target with drug therapy partly due to the fact
that it is not yet clear whether they are causal or merely an effect of the insulin
resistance state.

Skeletal muscles, like adipose tissue, also possess lipoprotein lipase, the
activity of which is normally suppressed by insulin. Metabolism. 1991
Feb;40(2):214-6. In insulin resistance, this activity is increased which could
contribute to the increased muscle triglyceride content, Metabolism. 1995
Jun;44(6):786-90. with resultant muscle insulin resistance. In fact, skeletal
muscle insulin sensitivity correlates closely with intramyocellular fat.
Diabetologia. 2001 Jul;44(7):824-33.

The PANCREATIC Scene

All patients by the time they reach IGT have some degree of insulin secretory
defect, since the pancreas has a huge reserve and hence coping ability
normally. Although there is a relative deficiency initially, by the stage when
fasting glucose rises above about 11.1 mmol/L (200 mg/dl) the deficiency of
insulin is in absolute terms. It makes sense to assume that the pancreatic beta
cell failure is secondary to insulin resistance of a prolonged duration, with
higher insulin resistance probably producing earlier failure in a susceptible
individual. Physiol Rev. 1995 Jul;75(3):473-86 The demonstration of offsprings
of type 2 diabetics being insulin resistant and hyperinsulinaemic is in keeping
with this. Ann Intern Med. 1990 Dec 15;113(12):909-15. But in recent times a
new assumption has been proposed, where the beta cell failure is thought to be
the primary genetic defect, and the resulting hyperglycaemia contributing to
glucotoxicity and later, insulin resistance. Endocr Rev. 1998 Aug;19(4):491-503.
Demonstration of first degree relatives of type 2 diabetics with normal glucose
tolerance but reduced insulin responses in the absence of insulin resistance
seems to be the strongest argument for this hypothesis. Metabolism. 2000
Oct;49(10):1318-25. Also, a 37% deficit in early insulin response has been
demonstrated in pre-diabetic subjects compared to non-diabetic subjects.
Diabetes Care. 2003 Mar;26(3):868-74. HOMA assessment of beta cell
function undertaken in the UKPDS study supports this by showing that beta
cell function is already reduced by 50% at the time of diagnosis of type 2
diabetic state. Diabetes. 1995 Nov;44(11):1249-58. The relentless progression
despite modalities to target insulin resistance (metformin) further lends
credence to this theory of a primary beta cell pathology. The process by which a
pancreatic dysfunction as the primary pathology could lead to insulin
resistance as a secondary event is difficult to explain. I would like to postulate
that a relative deficiency of insulin could upset the hepato-portal insulin to
glucagon ratio which might impact on fatty acid release in the periphery due to
excessive glucagon action. The increased fatty acid release could result in
hepatic steatosis and increased myocellular lipid content with development of
insulin resistance? (personal view). While much is known about the various
factors determining insulin resistance, much less is known about factors
determining insulin secretory ability or insulin secretory failure, which probably
stems from the fact that the hyperglycaemic clamp allows a reasonably accurate
measurement of insulin sensitivity while no such gold standard exists to
measure insulin secretory ability.

The primary defect in the beta cell could involve multiple aspects of insulin
synthesis and secretion which might under genetic control. Normally, insulin
secretion involves recognition of hyperglycaemia by the pancreas (glucose
sensing), glucose metabolism in the pancreatic cells, depolarisation of the beta
cell plasma membrane (closure of potassium channels), movement of preformed
secretory granules to the plasma membrane (involving microtubules and
microfilaments), followed by release of its contents (insulin, proinsulin, C
peptide) through fusion of the membranes (calcium influx). One or more of
these steps can be defective in a particular individual depending on the genetic
defect. Genetic defects have been described for the glucokinase gene, glucose
transporter 2 (GLUT-2), the insulin gene, the sulphonylurea receptor and the
mitochondrial genome. Diabetologia. 1996 Apr;39(4):375-82. Genetic defects
causing defective insulin action have also been identified including those for
GLUT-4, IRS-1. hexokinase II, FABP etc. While genetic analysis can be effective
in identifying defective genes in monogenic forms of diabetes, the mystery of
polygenic diabetes (type 2) still remains unraveled due to the heterogeneity of
the genotypes and the variable phenotypes in different populations.
Identification of a candidate gene(s) for type 2 diabetes by association would
then have to be the demonstrated to have a pathogenic role by quantitatively
relating it's malfunction to the insulin resistance or insulin deficiency in vivo.
Yet, it still remains unclear as to whether an insulin secretory defect or insulin
resistance contributes predominantly to the pathogenesis of type 2 diabetes.

Non-genetic factors may also play a role in the pancreatic endocrine

dysfunction. Down regulation of glucose transporters or oxidative stress-
induced alteration of transcription factors induced by hyperglycaemia
(glucotoxicity) Endocrinology. 2002 Feb;143(2):339-42. and impairment of beta
cell function by free fatty acids Diabetes. 2004 Feb;53 Suppl 1:S119-24.
especially in those with polymorphisms of the PPAR gamma receptors in the
beta cells Diabetes. 2001 May;50(5):1143-8. are also likely to play a role in the
beta cell dysfunction. Hyperglycaemia for 5 days has been shown to produce
increased beta cell apoptosis similar to that of overt diabetic state, Diabetes.
2001 Jun;50(6):1290-301. implicating glucotoxicity as a potent factor for beta
cell dysfunction. Hyperglycaemia results in increased production of reactive
oxygen species as superoxide which can activate the UCP-2 (uncoupling protein)
with resultant impaired ATP generation and insulin secretion. J Clin Invest.
2003 Dec;112(12):1831-42 In keeping with the lipotoxicity theory, lipid
infusion in subjects with a family history of type 2 diabetes reduced the first
phase response of insulin by 25% compared to controls and the second phase
by 42%. Diabetes. 2003 Oct;52(10):2461-74. While an increase in free fatty
acids over a short duration as 6 hours increases insulin secretion, longer
exposure seems to decrease the AIR (acute insulin response) by up to 50%.
Diabetologia. 1995 Nov;38(11):1295-9. A decreased response of the beta cells to
gut incretin hormones is thought to contribute to the pancreatic endocrine
secretory dysfunction, as show by reduced effect of GIP (glucose dependent
insulinotropic peptide) on insulin stimulation. A reduced response to the
predominant incretin GLP-1 has also been described. Islet Amyloid PolyPeptide
(IAPP) is found to be deposited in up to 90% of type 2 diabetic patients as
opposed to 10% of non- diabetic patients. The contribution of Islet amyloid
deposition towards this beta cell secretory dysfunction Nature. 1994 Apr
21;368(6473):756-60 is still open to discussion, Diabetes Res. 1988
Dec;9(4):151-9. but is generally thought to be representative of a degenerative
process or a secondary effect of hyperglycaemia Diabetes. 2003 Jan;52(1):102-
10. rather than a primary pathology. Yet increased fat intake seems to be
associated with higher islet amyloid associated polypeptide deposition in
experiments with transgenic mice expressing human IAPP. Diabetes. 2003
Feb;52(2):372-9. It remains to be clarified whether the size of the fibrils of
amyloid polypeptide can specifically influence apoptosis rates in human
pancreatic tissue invivo. Diabetes. 1999 Mar;48(3):491-8. TNF apart from
contributing to insulin resistance may also inhibit insulin signalling pathways
through stimulation of IL-1 release from intraislet macrophages in turn
inducing nitric oxide (free radical) production by beta cells. J Biol Chem. 1999
Jun 25;274(26):18702-8. The acute phase response of insulin (0-10 minutes)
to food is impaired when the fasting glucose increases above 6.4 mmol/L
accounting for the impaired suppression of hepatic glucose production (HGP)
described above. But in IGT and the early stages of T2DM, the later insulin
response (60-120 minutes) remains high and seems to be a compensatory
effort to control postprandial hyperglycaemia. Proinsulin processing in the
pancreas seems to be dysregulated in type 2 diabetes with increased proinsulin
to insulin ratios, which correlates with beta cell dysfunction and is in fact
predictive of type 2 diabetes development. Am J Med. 2003 Apr 15;114(6):438-
44. Aging is associated with a reduction in mitochondrial function and
oxidative phosphorylation. Reduction of ATP generation by oxidative
phosphorylation could compromise the beta cell secretory ability over time. This
could be superimposed on environmental stressors as obesity to result in
pancreatic endocrine insufficiency.
Over and above these functional abnormalities, the beta cell mass is also
noted to be decreased. In fact, reduction of pancreatic beta cell mass by up to a
third is well recognised in type 2 diabetics compared to non-obese individuals,
Diabetes Res. 1988 Dec;9(4):151-9. although this cannot in isolation explain the
80% reduction in secretory function seen in type 2 diabetics. The cell mass
has in fact been shown to be slightly increased in type 2 diabetics. Diabetologia.
1983 May;24(5):366-71 with impaired suppression of glucagon by
hyperglycaemia. Hyperglucagonaemia is a characteristic feature in type 2 (and
type I ) diabetes. Despite these, the changes in the cells are thought to be
secondary to the hyperglycaemia as these are reversible on restoring
euglycaemia.

The ADIPOCYTE Scene

In insulin resistant states as type 2 diabetes mellitus, the fat cells are resistant
to insulin, both for glucose uptake and suppression of lipolysis. J Clin
Endocrinol Metab. 1985 Nov;61(5):807-11 The latter defect results in increased
lipolysis in adipose tissue with chronically elevated free fatty acids (FFAs) which
in turn impairs insulin secretion, decreases glucose uptake in muscles, J Clin
Invest. 1983 Nov;72(5):1737-47. stimulates hepatic gluconeogenesis, increases
hepatic VLDL production and induces hepatic and muscular insulin
resistance. J Biol Chem. 2000 Mar 24;275(12):8456-60. Thus the adipocyte
defect might be more crucial in the pathogenesis of insulin resistance? Read
further about the role of adipose tissue........Insulin and glucose normally
stimulates adipocyte lipoprotein lipase activity while reducing muscle
lipoprotein lipase activity, thus directing fatty acids towards adipose tissue
rather than muscles. In obese patients, activation of lipoprotein lipase in
adipose tissue is delayed while LPL activity in muscle is increased, Proc Natl
Acad Sci U S A. 2001 Jun 19;98(13):7522-7. resulting in increased lipid
accumulation in muscles (increased intramyocellular lipid), with development of
the ectopic fat storage syndrome. The role of fatty acid transporter protein
(CD36) in regulation of fatty acid uptake in tissues, with implications on
development of insulin resistance in states of deficiency Lancet. 2001 Mar
3;357(9257):686-7 remains to be clarified.

Increased reductase activity of 11 beta HSD levels in fat seems to contribute to

locally raised cortisol levels which could facilitate increased adipocyte
proliferation with resultant adverse effects. Dysregulation of 11 HSD1 in
human obesity has been described and seems to be tissue specific. Increasing
BMI is associated with impaired 11-HSD1 activity, with the degree of
impairment correlating with visceral fat mass. J Clin Endocrinol Metab. 2004
Sep;89(9):4755-61. This down-regulation of 11 HSD1 activity in the obese
could be protective against development of insulin resistance. Type 2 diabetic
patients do not show this BMI related change in 11 HSD1 activity J Clin
Endocrinol Metab. 2004 Sep;89(9):4755-61 and it can be postulated that a lack
of down-regulation of 11 HSD1 in obese patients could facilitate development
of diabetes.

The VASCULAR Scene

Normally insulin produces nitric oxide dependent vasodilatation of the

peripheral resistance vessels. Am J Physiol. 1994 Aug;267(2 Pt 1):E187-202
Endothelium dependent vasodilatation has been shown to be defective in
insulin resistant states. Eur J Clin Invest. 2001 Dec;31(12):1013-4.
Hyperinsulinism which characterises insulin resistance is thought to produce
vascular damage with predilection for atherosclerosis though induction of
vascular smooth muscle proliferation. The hyperinsulinism of insulin resistance
stimulates the MAP kinase pathway excessively, resulting in increased growth
and proliferation of vascular smooth muscle cells, with increased collagen
formation and release of growth and chemotactic factors which facilitate
atherosclerosis. Lowering of hyperinsulinaemia using modalities as metformin
would thus be expected to improve atherosclerosis related macrovascular
disease as opposed to exogenous insulin or insulin secretagogue therapies, as
demonstrated in the UKPDS trial. Lancet. 1998 Sep 12;352(9131):854-65.
Insulin normally decreases vagal tone while increasing sympathetic drive, and
hence hyperinsulinism might contribute to the increased sympathetic drive
seen in insulin-resistant obese J Clin Invest. 1994 Jun;93(6):2365-71. or
perhaps not? J Clin Endocrinol Metab. 2001 Mar;86(3):1403-9

Procoagulant factors:

Platelets:

Insulin normally inhibits platelet aggregation. Diabetes Care. 1998

Jan;21(1):121-6 Platelet vascular mechanism are activated in diabetes mellitus
evidenced by increase in beta thromboglobulin, platelet factor 4, thromboxane
A4 and B2, ICAM 1 and E- selectin and decreased prostaglandin12. Platelets
in diabetics have an increased sensitivity to activation under high shear stress.
The increased procoagulant nature of the platelets is demonstrated by an
increased tendency to ADP induced aggregation.
Fibrinogen:

Fibrinogen levels are raised in diabetes mellitus. Levels are particularly raised
due to chronic hypersecretion in those with prolonged poor metabolic control.
Hence improved diabetic control should theoretically decrease fibrinogen levels
and improve the coagulant status.

Increased fibrinogen levels increase blood viscosity with increased tissue

deposition of bigger fibrin clots with stimulation of atherosclerosis. Glycated
fibrinogen deposition is probably greater than fibrinogen itself. due to decreased
susceptibility to plasmin. These could have impact on macro and microvascular
disease initiation and progression. Metformin may have a positive influence on
the fibrin structure and the cross linking of fibrin by factor 12 . This improves
the hypofibrinolytic state of diabetes.

PAI-1:

High levels of plasminogen activator inhibitor which inhibits fibrinolysis is a

feature of type 2 diabetes mellitus. This is an added risk factor for
macrovascular disease. Although both t-PA and PAI-1 activity are increased in
diabetics, the latter is clearly overpowering due to the net reduction of the free
fibrinolytic activity. It is interesting to note in this juncture that in type 1
diabetics without complications PAI-1 activity is normal but when complications
occur, the levels are usually high. Metformin reduces PAI-1 by 20%.

Glycated LDL:

An independent factor increasing PAI-1.

Treatment options

The knowledge of the multiple sites of insulin resistance as well as the multiple
abnormalities associated with insulin resistance ( low HDL, high triglycerides,
hypertension, obesity, increased platelet aggregation, increased procoagulant
tendency) with or without hyperglycaemia, should prompt a multi-pronged
approach to treating this multi-faceted disease.

INSULIN RESISTANCE- TREATMENT OPTIONS:

Weight loss Exercise Metformin Thiazolidinediones

Anti Obesity Medications:

Body weight is the commonest and easily measurable indicator of insulin
resistance. Combating obesity brings immense benefits as sited elsewhere in
this site. Most studies (DPP, Finnish DPS, Da Qing, XENDOS) have
demonstrated the positive effect of weight loss on improved glucose tolerance
with prevention of progression of IGT to T2DM. . In the XENDOS study involving
3304 patients (80% with IGT) for 4 years, the orlistat group had a 37% risk
reduction in progression from IGT to T2DM (weight reduction in placebo and
orlistat group: 7.5 vs. 11.4 kg; Conversion rate from IGT to T2DM in placebo
and orlistat groups: 9% vs. 6.2% respectively) Diabetes Obes Metab. 2003
Sep;5(5):356. Weight loss improves vascular response to L- arginine, reduces
fasting insulin concentrations, and reduces IL 6 and TNF levels. Increasing
the dietary carbohydrate with lowering of dietary fat has been shown to improve
glucose tolerance secondary to an increase in insulin secretion and an
improvement in insulin sensitivity in older people J Clin Endocrinol Metab. 1988
Nov;67(5):951-7. and type 2 diabetics. N Engl J Med. 1971 Mar 11;284(10):521-
4.

Exercise

Both aerobic and resistance training exercises improve insulin sensitivity, but
the beneficial effects of exercise tend to decrease after a few days of inactivity.
Studies have shown that physical activity N Engl J Med. 1991 Jul 18;325(3):147-
52 and fitness levels Ann Intern Med. 1999 Jan 19;130(2):89-96 are inversely
associated with incidence of type 2 diabetes independent of BMI. So, how does
exercise produce an improvement in insulin resistance? Regular exercise may
increase translocation of GLUT-4 glucose transporters in skeletal muscle cells
partly related to the increased skeletal muscle blood flow J Clin Endocrinol
Metab. 1995 Aug;80(8):2437-46. and AMPK (5'adenosine monophosphate
activated protein kinase) activation Diabetes. 1999 Aug;48(8):1667-71. thus
improving glucose uptake. The ability of insulin to increase skeletal muscle
blood flow seems to be improved with exercise in normals and insulin resistant
subjects. Diabetes. 1995 Sep;44(9):1010-20 , and the increased blood flow
may improve local availability of insulin as well. Exercise has been associated
with increased release of local bradykinin which may have stimulatory effects
on glucose uptake. Diabetes. 1998 Apr;47(4):550-8 Exercise without weight
loss significantly reduces visceral fat compared to controls. Exercise-induced
weight loss reduces total fat to a greater extent than diet induced weight loss.

Metformin:
Metformin has been shown to improve muscle insulin sensitivity measured with
the euglycaemic insulin clamp in type 2 diabetics. Metformin also improves
insulin sensitivity and normalises glycogen synthesis in the muscle in insulin
resistant normoglycaemic first degree relatives of individuals with type 2
diabetes mellitus. Metformin may activate AMP kinase leading to enhanced
basal and insulin stimulated glucose transport in muscle

Metformin improves hepatic insulin sensitivity. Basal HGP was decreased by

20% in T2DM treated with metformin- interestingly despite a reduction in
fasting plasma insulin. Metformin does this by improving insulin receptor
tyrosine phosphorylation and enhances glucose transport. Activation of AMP
kinase in liver causes inhibition of hepatic glucose production and decreased
expression of a number of genes involved in hepatic free fatty acid and VLDL
synthesis. The VLDL synthesis reduction may also be partly mediated through
a decrease in acetyl Co A carboxylase activity. All these could be involved in the
efficacy of metformin in retarding the progression of IGT to T2DM as shown in
the DPP study. Combating insulin resistance with decreased FFA and VLDL
synthesis could explain the cardiovascular mortality reduction in obese
diabetics demonstrated in the UKPDS. Read more on Metformin

Thiazolidinediones:

Rosiglitazone and Pioglitazone are the major players in this group at present.
Thiazolidinediones improve insulin sensitivity in both liver and muscle. They
(rosiglitazone and pioglitazone) augment insulin stimulated muscle glucose
uptake and enhance basal and insulin mediated suppression of HGP.
Improvement in glycaemia may contribute to improved beta cell function.

Both thiazolidinediones were shown to produce a 35% increase in insulin

mediated muscle glucose disposal in T2DM patients using a euglycaemic insulin
clamp. Treatment of T2DM with rosiglitazone almost completely reversed the
severe impairment in IRS-1 tyrosine phosphorylation, and markedly increased
PI-3 kinase activity. This closely correlated with improvement in muscle insulin
sensitivity and muscle glycogen synthesis measured with euglycaemic clamp.
The above mechanisms imply that thiazolidinediones may be effective in
preventing/delaying progression of IGT to T2DM.

The thiazolidinediones also seem to enhance insulin secretion probably through

increasing glucose uptake by the beta cell. Diabetologia. 1995 Jan;38(1):24-30.
They have also been shown to preserve beta cell function in diabetic animal
models. The beneficial effect of thiazolidinediones may partly be related to the
favourable fat redistribution since this happens despite a consistent finding of
weight gain! They reduce hepatic and visceral fat, while increasing
subcutaneous fat. The effect on intramyocellular fat is controversial with
studies for and against such an action. Thiazolidinediones seem to consistently
lower the plasma FFA concentration by 25-35%. Diabetes Care. 2001
Apr;24(4):710-9. This reduction in free fatty acid levels may be brought about
partly by improving insulin sensitivity and partly through suppression of TNF
alpha expression in adipose tissue -which normally facilitates lipolysis- by
thiazolidinediones. Diabetes Obes Metab. 2001 Aug;3 Suppl 1:S11-9. A direct
protective effect of beta cells from lipotoxicity seems to be offered by glitazones
in in vitro studies. Am J Physiol Endocrinol Metab. 2004 Apr;286(4):E560-7

Triglyceride accumulation in beta cells of pancreas causes in increase in fatty

acyl coA levels with increased ceramide synthesis which increases NO resulting
in beta cell apoptosis. It is proposed that improvement of triglyceride content in
the pancreatic beta cells brought about by thiazolidinedione therapy in the rats
might explain the decreased beta cell apoptosis with the possibility of
preservation of pancreatic islet function for longer. J Biol Chem. 1998 Feb
6;273(6):3547-50. The increased proinsulin to insulin ratios, which correlates
with beta cell dysfunction and is predictive of type 2 diabetes development, Am
J Med. 2003 Apr 15;114(6):438-44. is also improved by thiazolidinediones.
Diabet Med. 2004 Jun;21(6):568-76.

Studies showing clinical efficacy of thiazolidinediones:

In the thiazolidinedione arm of DPP (troglitazone) where patients were exposed

to the drug for 10 months, there was a 23% decrease in the conversion rate of
IGT to T2DM.

TRIPOD study involving 235 women with a history of GDM (two third with IGT),
where the women were treated with troglitazone for 30 months, the drug did
better than placebo (12.3% per year converting from IGT to T2DM in the placebo
group as opposed to 5.4% in the troglitazone group; p<0.001) Diabetes Metab.
2003 Nov;29(5):547-53. The PIPOD study using pioglitazone will be looking at
similar benefits.

Ongoing studies with the combination of Rosiglitazone and Ramipril (DREAM

trial-Diabetes REduction Approaches with Ramipril and Rosiglitazone-4000.
IGT patients with established CVS disease for 3 years) will hopefully clarify the
role of these drugs in combating insulin resistance and glucose intolerance.
Diabetologia. 2004 Sep;47(9):1519-27.

Read AHA and ADA consensus statement on Thiazolidinedione use

Sulphonylureas:
Among the sulphonylureas, the third generation sulphonylurea (Glimiperide)
seems to have a more favourable cardiovascular profile. Horm Metab Res. 1996
Sep;28(9):496-507. Glimiperide seems to improve glycaemia to similar levels as
the second generation sulphonylureas despite lower insulinotropic activity.
Diabetes Res Clin Pract. 1995 Aug;28 Suppl:S115-37. This is thought to imply
extra-pancreatic effects of Glimiperide through favouring peripheral glucose
uptake as well as by augmenting first phase insulin secretion.
Pharmacotherapy. 2004 May;24(5):606-20.

The term Glucotoxicity has been coined to explain the beta cell failure as well as
peripheral insulin resistance in type 2 diabetes. Sulphonylureas may partly
exert their beneficial effect through improvement of glucotoxicity. Glucotoxicity
implies chronic elevation of plasma glucose levels inducing insulin resistance
and impairing beta cell function by local toxicity. High levels of glucose down-
regulates the glucose transport system in the muscle while up-regulating
glucose-6- phosphatase in the liver with increased hepatic glucose production,
both contributing to insulin resistance at the respective sites. An ongoing study
with Nateglinide should address the issue of postprandial glucose reduction
and improvement in insulin resistance effects. The fact that glycaemic control
did not produce statistically significant improvement in Cardiovascular
outcomes in the UKPDS suggests that tackling the glycaemic abnormality is
probably not the whole answer to insulin resistance management.

ACE Inhibitors:

ACE Inhibitors improve muscle blood flow and increase muscle glucose uptake
(increase GLUT4 activity). FEBS Lett. 2004 Oct 22;576(3):492-7. They suppress
brain sympathetic activity thus improving insulin sensitivity. They may have an
effect on the tissue ACE demonstrated in pancreatic beta cells. Increasing the
bradykinin and prostaglandins in the muscle has been shown to improve
insulin sensitivity of muscle and this could be a possible mechanism. Diabetes.
1998 Apr;47(4):550-8 Counteracting the deleterious effects of Angiotensin II
in the adipose tissue, and recruiting new adipocytes by facilitating adipocyte
differentiation could be yet another mechanism of action of ACE inhibitors.
Diabetes Metab. 2004 Dec;30(6):498-505.

Future therapy options:

Agents to improve insulin signalling, using activators of insulin receptor

tyrosine kinase activity Science. 1999 May 7;284(5416):974-7. might
become possible in the future. Reducing free fatty acid levels using agents
(etomoxir) to inhibit carnitine palmitoyl transferase I (CPT-1) has the potential
to improve plasma triglyceride levels Metabolism. 1991 Nov;40(11):1185-90
and producing modest improvements in glycaemia through inhibition of hepatic
gluconeogenesis, although this could potentially pose problems with poor
response to hypoglycemia. Vanadium compounds have been shown to hold
some promise in decreasing endogenous glucose production as well as
increasing peripheral glucose disposal with reduction in lipolysis. J Clin Invest.
1995 Jun;95(6):2501-9. Glucagon antagonists to counter the actions of
glucagon is another potential area for research in this field. Expert Opin Ther
Targets. 2005 Jun;9(3):593-600. Since reactive oxygen species as superoxides
are recognised to produce functional beta cell impairment, J Clin Invest. 2003
Dec;112(12):1831-42 antioxidants could theoretically hold promise to preserve
beta cell function.

Is insulin resistance really bad?

Various questions have troubled the medical community for sometime. Is

insulin resistance the consequence of obesity? Or does insulin resistance lead
to obesity? Did the obese individual have a NEED for insulin resistance as a
protective phenomenon? Or in other words, is insulin resistance a good thing
that has gone terribly wrong?

The lipotoxicity hypothesis assumes the latter view. Excess carbohydrates are
stored as glycogen normally. When glycogen stores are replete, further fate of
the carbohydrates is entry into the lipogenic pathway (conversion to acetyl coA
and then malonyl CoA). Malonyl coA inhibits fatty oxidation (lipolysis) by beta-
oxidation, through inhibition of the CPT-1 (carnitine palmitoyl transferase 1)
enzyme, while favouring fat deposition ( lipogenesis), while the cell which is
insulin sensitive continues to utilize glucose for its energy needs. The proposed
disadvantage of this scenario is that the fat that does not undergo beta
oxidation here, can be metabolised by other pathways leading to toxic products
facilitating apoptosis and lipotoxicity. Annu Rev Med. 2002;53:319-36.
Development of insulin resistance (to the uptake of glucose into cells) results in
diversion of the stored triglycerides into the preferred beta oxidation pathway
avoiding generation of toxic substances including nitric oxide and ceramide.
Trends Endocrinol Metab. 2003 Nov;14(9):398-403. But if this was to be as
simplistic as it sounds, insulin resistance would have ultimately produced total
lipolysis thus limiting the fat accumulation and restoring insulin sensitivity! It
is important to realise that it is postulated that insulin resistance in this
context may be selective for glucose uptake and not for lipogenesis. In other
words, the cell remains sensitive to the lipogenic action of insulin through
mechanisms as SREBP1c up regulation, Endocr Rev. 2002 Apr;23(2):201-29.
facilitating continued deposition of fat as long as excess dietary supply of
carbohydrates or calories is maintained.

This page was last updated on: 07/03/2007