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In 1949 Himsworth stated that the efficiency of insulin vary at different times in the diabetic
patient suggesting that patient with diabetes could be differentiated into insulin sensitive and insensitive groups. Yellow and Berson (1960) found that insulin levels were higher in patients with adult onset diabetes. The two observations gave origin to the concept of insulin resistance.
Insulin resistance can be defined as a state of lack of sensitivity or responsiveness of the tissues to insulin leading to impaired hypoglycemic action of insulin. It is said to be present in a diabetic patient when insulin requirement exceed 200 units/day in the absence of diabetic ketoacidosis or infection.
Mechanism of action of insulin
In order to understand the mechanisms leading to insulin resistance it is essential to have a knowledge of insulin's mechanism of action. Insulin interacts with its specific cell surface receptors. Binding of insulin to sub unit of the receptor induces autophosphorylation of the B subunit and the activation of endogenous tyrosinkinase activity, which triggers a phosphorylation/dephosphorylatio cascade of endogenous substrates. Insulin induced G-proteins activity acts as a transducer of insulin signalling to induce a phospholipid cascade via activation of phospholipase C, leading to generation of several mediators which results in the biological effects of insulin on regulation of gene expression, enzyme activity, glucose transporters etc. Abnormalities anywhere along this multifactorial sequence can lead to insulin resistance.
Causes of insulin resistance may be immunologic or non
immunologic
Immunologic Causes
(A) Idiopathic (B) Lymphatic leukemia (C) Destruction of insulin at the injection site
(D) Autoreceptor antibodies.
Non-immunologic Causes
(A) Obesity
(B) Endocrinopathies - Hyperthyroidism, Acromegaly, Cushings disease,
Pheochromocytoma
(C) Cirrhosis of liver
(D) Hemochromatosis.
Depending on the molecular mechanisms involved insulin resistance may be -
(a) Prereceptor (b) Receptor or (c) Post receptor
(a) Prereceptor resistance:
Insulin resistance due to prereceptor causes involves –
1. Insulin Antibodies
These are usually of IgG type and develop in most diabetic patients treated with insulin for
as little as a few weeks.
Factors determining immunogenicity -
(i) Species - Bovine insulins are more immune genie.
(ii) Addition of protein increases immunogenicity.
(iii) Immunogenicity is more for conventional insulins,
(iv) pH - Acidity increases immunogenicity.
The titre of antibodies vary in different individuals. Not all patients with insulin binding
antibodies show significant degrees of insulin resistance and is most likely due to the fact that in these patients sufficient amounts of free insulin are in equilibrium with antibody bound hormone to maintain glucose homeostasis. Those with insulin resistance will usually have high titres of antibodies. The onset may be abrupt resulting in ketoacidosis, but usually gradual presenting with uncontrollable hyperglycemia.
2. Local blocking antibodies
This causes destruction of hormone at the site of injection. Addition of protease inhibitor
(Aprotinin) to the insulin mixture may be helpful. The injection site and route may also be changed, intravenously or Intraperitonealy.
3. Abnormal Insulin molecule
This is due to mutations in the insulin gene resulting in the production of a defective
insulin. In this syndrome the patients are only resistant to their endogenous insulin and not to exogenous insulin.
4. Excess of counter insulin factors as in growth hormone hypersecretion, excess of exogenous or endogenous glucocorticoids, states of catecholamineragic hyperactivity, hyperlipidemia and accumulation of diabetes associated peptide (DAP) or amylin in the pancreas of patients with type II diabetes.
Receptor resistance
Various mechanisms are described -
(a) Decrease in the number of insulin receptors -
This defect has been defined in patients with type A insulin resistance, obesity,
leprechaunism and Rabson-mendenhall syndrome, generalized lipodystrophy and lipoatrophy.
Four different molecular mechanisms have been suggested for this biochemical
abnormality.
(1) Decreased levels of insulin mRNA - due to mutation at codon 897 in exon 14 of the
insulin receptor.
(2) Impaired transport of insulin receptor to the cell surface- due to single aminoacid
substitution (Val for Phe) at codon 382 of the @ subunit.
(3) Truncated receptor - due to a nonsense mutation leading to deletion of the carboxy
terminal part of the @ subunit.
(4) Accelerated receptor degradation - due to a mis-sense mutation at codon 460 of the
subunit which changes the pH sensitivity of the receptor.
(b) Decreased insulin binding affinity -
This is due to a mutation substituting Serine for Arginine or Prolinin for leucine. As a result
of this the proteolytic processing of the receptor precursor into its two subunits is prevented. The uncleaved precursor has a decreased affinity for insulin.
(c) Insulin receptor kinase defects -
This may be due to defects in tyrosin kinase activity due to mutation or deletion in the
insulin receptor gene. e.g. A mis-sense mutation at codon 1008 results in the abolishment of tyrosine kinase activity, while a mutation at codon 1200 in the B subunit decreases the activity of tyrosin kinase.
Post receptor resistance
The pre-receptor and receptor abnormalities described, may not lirectly account for the
insulin resistance most commonly icountered. Post-receptor abnormalities therefore may account for the major portion of insulin resistance. The probable sites at which iefects can occur are (i) Dysfunctional signal transducing mechanism Although, theoretically possible, the importance of the potential Signaling mechanisms has not been fully investigated and it contribution to insulin resistance is not clearly established, (ii) .Impairment of cellular glucose transport :- Two classes of glucose ransporters have been described in mammalian cells: the Na+ - glucose cotransporter, necessary for glucose uptake from the GIT and lumen of the proximal tubule of the kidney and facilatative transporters- these are widely distributed and play a major role in the transport of glucose across cell membranes.
Insulin stimulation of glucose transport is associated with a reversible and dose
dependent recruitinent of glucose transporters from a large intracellular pool to the cell membrane. Experimental studies in rat adipocytes indicate that there is little decrease in the intrinsic activity of glucose transporters in plasma membranes in insulin resistance. Alteration in the glucose transporters translocation appears to be major defect contributing to the insulin resistance states. In addition a reduction in the number of glucose transporters due to impaired gene expression has been identified as one of the causes of insulin resistance in obese subjects and NIDDM patients, (iii) Reduced enzymatic activities in intracellular glucose metabolism :- There are two major metabolic pathways for glucose utilisation - oxidative an non-oxidative metabolism. There is evidence of impaired insulin stimulation of both oxidative and non- oxidative metabolism in diabetic patients in vivo and in cell systems.
In vitro studies, using adipocytes from IDDM patients have demonstrated a decrease in
the enzymatic activity of pyruvate dehydrogenase and glycogen syntnase. These enzymatic defects in NIDDM patients could be a contributing cause to insulin resistance.
A few clinical syndromes of insulin resistance
In some of these conditions more than one of the mechanisms described above are
involved.-
a) Obesity-
In obesity, decrease in number of receptors is associated with a failure to activate the
tyrosin kinase - a post receptor abnormality.
b) Conditions with Acanthosis nigricans and insulin resistance-This may be type A or
type B Type A is found in tall young women and there is a tendency for hirsuitism and
abnormalities of reproductive tract like polycystic ovaries. Many mutations in the insulin
receptor have been found in this patients. Type B is found in older women with
immunologic disease. Antibodies to insulin receptors can be demonstrated. Arthralgias
alopecia, enlarged salivary glands and protienuria are other features.
c) Lipodystrophy-
It may be partial or total, congenital acquired. There is absence of subcutaneous fact
associated with hyperglycemia, hyperlipidemia
leading to erruptive xanthomas and hyermetabolism without hyperthyroidism. Ketosis does
not occur. Hepatomegaly, spleenomegaly and cardiomegaly usually accompany. Hirsuitism, Lymphadenopathy, Prominent external genitalia excessive pigmentation and mental retardation are other features. Insulin resistance is due to reduced number of receptors, diminished affinity of receptor for insulin and there is post receptor defects also.
dl Werner syndrome-Patients with this condition have slender extremities but stocky truck,
premature greyness and baldness, premature atherosclerosis, cataract, skin atrophy and hypokeratosis.
There is also precocious puberty, hirsuitism and hypogonadism.
e) Alstrom syndrome -
It is characterised by autosomal recessive inheritance, retinal degeneration, nerve
deafness and multiple endocrine organ resistance. Other features are baldness, hyperuricemia, hypertriglyceridemia and-aminoacidurea.
f) Leprechaunism-
This is probably a severe form of total lipodystrophy. It is characterised by Elfin fascies
and loss of subcutaneous fat, thickened skin and hirsutisum. Insulin resistance is due to defects in subunits of insulin receptor causing markedly diminished expression of receptors on plasma membranes.
g) Others -
Insulin resistance due to hormone excess, (Acromegaly, Gushing syndrome) Mytonic
dystrophy and thalassemia major.
What is pseudo insulin resistance
With increased dose of insulin Hypoglycemia develops. In order to correct Hypoglycemia
patient eats excessively. Counter regulatory hormones also increase. This result in Hyperglycemia and increase in the requirement of insulin.
Management of insulin resistance in general
The following guidelines may be observed -
(a) In non-immune type treatment of the underlying cause is required.
(b) Change the species of insulin - e.g. Beaf insulin to pork insulin-
(c) Use purified insulin, which is less antigenic.
(d) Use human insulin.
(e) Use steroids 60-80 mgm prednesolone for 10 days. If human insulin is not available.
Stops steroids if there is no response in 10 days.
(f) Sulphonylurea or Biguanides improve insulin receptor sensitivity. Hence can be used
along with insulin for a short period.
(g) Role of diet restriction. Fasting for 2- 3 days improve the insulin action by increasing
the affinity of insulin receptor in obese diabetic patients.
Conclusion
Insulin resistance represents a heterogeneous syndrome with different pathogenetic
mechanism viz, Pre- receptor, Receptor and Post receptor. It appears that in the vast majority of patients with insulin resistance, it is due to impaired cellular insulin action at the post receptor level.
REFERENCES
(1) J.Serrano, C-M. Mateo, J.KCaro: Insulin resistance - cellular and molecular
mechanisms. Recent Advances in endocrinology and metabolism. No.4, pp.167,1992.
(2) John. A. Galloway, Rubin Bressler, MCNA Diabetes Mellitus, July 1978, pp.663.
(3) Daniel W. Foster, Harsons principles of internal medicine 14th Edition, pp.2079.
(4) Malcolm Nattrass, Julio V Saintiago : Recent advances in diabetes, No.l, pp.27-40,
1984.
(5) P.C.Bullar, Insulin resistance clinical implication. Recent advances in endocrinology,
No.4, pp.185, 1992,
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