Insulin resistance
| Insulin resistance | ||
| MeSH | C18.452.394.968.500 | |
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Insulin resistance Microchapters |
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Diagnosis |
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Treatment |
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Case Studies |
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Insulin resistance On the Web |
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American Roentgen Ray Society Images of Insulin resistance |
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Omar Elshafei, MD[2] Dayana Davidis, M.D. [3]
Overview
Insulin resistance is a state in which normal circulating concentrations of insulin produce a subnormal biological response in target tissues, principally skeletal muscle, liver and adipose tissue. It is not a disease in itself but a pathophysiological state that underlies a cluster of disorders including type 2 diabetes mellitus, metabolic syndrome, metabolic dysfunction-associated steatotic liver disease, polycystic ovary syndrome and atherosclerosis.
In the great majority of affected people, insulin resistance arises from the interaction of positive energy balance with a genetically determined limit on the capacity of peripheral adipose tissue to store triglyceride safely. When that limit is exceeded, lipid accumulates ectopically in liver and skeletal muscle, where lipid intermediates interfere with post-receptor insulin signalling. As long as the beta cell can increase insulin output, glucose tolerance is preserved at the cost of chronic hyperinsulinemia; when compensation fails, impaired glucose tolerance and then overt diabetes mellitus appear. A minority of patients have rare monogenic or autoimmune syndromes in which insulin resistance is extreme and dominates the clinical picture.
There is no universally accepted diagnostic threshold for insulin resistance, and no laboratory index of insulin sensitivity is recommended for routine clinical diagnosis. The hyperinsulinemic euglycemic clamp remains the reference method for research, while surrogate indices derived from fasting or post-load samples are used in epidemiological work. In practice, the condition is recognised clinically by its associated phenotype and is managed by treating the associated conditions: weight reduction, increased physical activity, and pharmacological or surgical therapy directed at adiposity, dysglycemia, dyslipidemia and cardiovascular risk.
Historical Perspective
The concept that diabetes mellitus could be divided into insulin-sensitive and insulin-insensitive forms was proposed by Harold Himsworth in 1936, on the basis of differing glycaemic responses to combined oral glucose and intravenous insulin.
The first widely accepted biochemical explanation for the phenomenon was the glucose-fatty acid cycle described by Randle and colleagues in 1963, which proposed that increased fatty acid oxidation inhibits glucose utilisation in muscle through substrate competition.[1]
Quantitative measurement became possible with the introduction of the glucose clamp technique by DeFronzo, Tobin and Andres in 1979, which allowed beta cell sensitivity to glucose and tissue sensitivity to insulin to be measured independently.[2] Simplified estimation from fasting samples followed with the homeostasis model assessment in 1985.[3]
In his 1988 Banting Lecture, Reaven placed insulin resistance at the centre of a cluster of abnormalities comprising glucose intolerance, hyperinsulinemia, raised triglycerides, reduced HDL cholesterol and hypertension, which he termed Syndrome X and which became the basis of the modern concept of the metabolic syndrome.[4]
A molecular link between adiposity and impaired insulin action was established in 1993, when adipose tissue expression of tumor necrosis factor-alpha was shown to contribute directly to obesity-linked insulin resistance.[5]
Subsequent work reframed insulin resistance as a disorder of ectopic lipid deposition and of lipid-mediated interference with post-receptor signalling,[6] and integrative genomic analysis established that the common polygenic form and rare severe forms share a final common mechanism of limited peripheral adipose storage capacity.[7]
Classification
Insulin resistance may be classified by mechanism, by severity, and by whether it is a physiological adaptation or a pathological state.
Data-driven cluster analysis of adult-onset diabetes has defined a severe insulin-resistant subgroup with the highest risk of diabetic nephropathy,[8] and comparable pathophysiology-based subphenotypes have been described in people at elevated risk before diabetes develops.[9]
Rare severe forms are conventionally separated into primary disorders of insulin signalling and disorders of adipose tissue development or function,[10][11] together with an autoimmune form caused by autoantibodies to the insulin receptor.[12]
| Category | Subtype | Representative examples and features |
|---|---|---|
| Physiological | Life-stage related | Puberty, pregnancy (particularly the third trimester), ageing. Reversible and not usually pathological in isolation. |
| Physiological | Stress related | Acute illness, sepsis, trauma, major surgery, glucocorticoid stress response. |
| Common (polygenic and acquired) | Adiposity-associated | The dominant form. Associated with central obesity, physical inactivity and a polygenic background of at least 53 genomic regions linked to reduced peripheral adipose storage capacity.[7] |
| Common (polygenic and acquired) | Cluster-defined | Severe insulin-resistant diabetes, characterised by high body mass index and high HOMA2-IR, with the highest risk of diabetic nephropathy.[8][9] |
| Severe insulin resistance syndromes | Primary defects of insulin signalling | Insulin receptor (INSR) mutations: type A insulin resistance, Rabson-Mendenhall syndrome, Donohue syndrome (leprechaunism); post-receptor defects such as AKT2 mutations.[10] |
| Severe insulin resistance syndromes | Disorders of adipose development or function | Congenital generalised lipodystrophy, familial partial lipodystrophy, acquired generalised and partial lipodystrophy.[11][10] |
| Autoimmune | Type B insulin resistance | Autoantibodies directed against the insulin receptor, producing extreme hyperglycemia, hypercatabolism, severe acanthosis nigricans and hyperandrogenism in women.[12] |
Pathophysiology
Normal insulin action
Insulin binding to the insulin receptor triggers receptor autophosphorylation and tyrosine phosphorylation of insulin receptor substrate proteins, activating phosphoinositide 3-kinase and AKT2. Downstream effects include translocation of GLUT4 to the plasma membrane in skeletal muscle and adipose tissue, stimulation of glycogen synthesis, suppression of hepatic gluconeogenesis, and suppression of adipose lipolysis.[13]
Ectopic lipid and lipid-induced signalling defects
When the storage capacity of peripheral subcutaneous adipose tissue is exceeded, triglyceride accumulates in liver and skeletal muscle. Accumulation of diacylglycerol activates protein kinase C isoforms that inhibit insulin receptor and insulin receptor substrate signalling, and ceramide species impair AKT2 activation. The result is tissue-selective failure of the metabolic limb of insulin signalling.[6][13] The historical glucose-fatty acid cycle remains relevant as a description of substrate competition, but is no longer regarded as the principal mechanism of insulin resistance in humans.[1][6]
Adipose storage capacity
Genomic analysis of insulin resistance phenotypes has shown that loci associated with higher fasting insulin, lower HDL cholesterol and higher triglycerides are associated with lower peripheral adipose mass, and that these same loci contribute polygenically to familial partial lipodystrophy type 1. This provides direct evidence that common and severe insulin resistance share a mechanism of constrained adipose expandability rather than simple excess fat mass.[7]
Inflammation
Adipose tissue in obesity shows macrophage infiltration and increased expression of pro-inflammatory cytokines including tumor necrosis factor-alpha, which impairs insulin signalling and contributes to systemic insulin resistance.[5][13]
Selective resistance and its consequences
Resistance affects the metabolic (phosphoinositide 3-kinase/AKT) limb of insulin signalling more than the mitogenic limb. Persistent hyperinsulinemia therefore continues to drive hepatic de novo lipogenesis, renal sodium retention and ovarian androgen production, which explains the co-segregation of insulin resistance with hypertriglyceridemia, hypertension and hyperandrogenism.[13][4]
Pathophysiological sequence
| Positive energy balance combined with genetically limited peripheral adipose tissue expandability | |||||||||||||
| Ectopic triglyceride deposition in liver and skeletal muscle with adipose tissue inflammation | |||||||||||||
| Accumulation of diacylglycerol and ceramide with activation of protein kinase C isoforms | |||||||||||||
| Impaired insulin receptor substrate signalling through phosphoinositide 3-kinase and AKT2 | |||||||||||||
| Hepatic: failure to suppress gluconeogenesis with increased de novo lipogenesis | Muscle: reduced GLUT4 translocation and glycogen synthesis | ||||||||||||
| Compensatory hyperinsulinemia with preserved glucose tolerance | |||||||||||||
| Beta cell compensation fails: impaired glucose tolerance then type 2 diabetes mellitus | |||||||||||||
Causes
Causes are grouped below as physiological, adiposity-related and lifestyle, endocrine, drug induced, genetic, autoimmune and other.
Experimental sleep restriction reduces adipose tissue insulin sensitivity in healthy adults.[14] Endocrine causes include hypercortisolism[15] and polycystic ovary syndrome.[16] Among drug-induced causes, statin therapy is associated with a modest increase in incident diabetes mellitus in a collaborative meta-analysis of 13 randomised trials, an effect judged small relative to cardiovascular benefit.[17] Metabolic dysfunction-associated steatotic liver disease is both a consequence and a marker of the insulin-resistant state.[18]
| Category | Causes |
|---|---|
| Physiological | Puberty; pregnancy; ageing; acute illness, sepsis, burn injury and major surgery. |
| Adiposity and lifestyle | Central and visceral obesity; physical inactivity; excess energy intake; short or disrupted sleep.[14] |
| Endocrine | Cushing's syndrome and Cushing's disease;[15] acromegaly; pheochromocytoma; glucagonoma; hyperthyroidism; polycystic ovary syndrome.[16] |
| Drug induced | Glucocorticoids; atypical antipsychotic agents; thiazide diuretics; protease inhibitors and other antiretroviral agents; calcineurin inhibitors; niacin; statins.[17] |
| Genetic | Mutations of INSR producing type A insulin resistance, Rabson-Mendenhall syndrome and Donohue syndrome; post-receptor defects such as AKT2 and TBC1D4; monogenic lipodystrophy syndromes including LMNA, PPARG, AGPAT2 and BSCL2; syndromic forms such as Alström syndrome.[10][11] |
| Autoimmune | Insulin receptor autoantibodies (type B insulin resistance), often in association with systemic lupus erythematosus and other connective tissue disease.[12] |
| Other | Metabolic dysfunction-associated steatotic liver disease;[18] obstructive sleep apnea; chronic kidney disease; hemochromatosis; chronic hepatitis C. |
Differentiating Insulin Resistance from other Diseases
Insulin resistance is a mechanism common to many conditions rather than a stand-alone diagnosis. The metabolic syndrome is a separate defined construct requiring three of five harmonised criteria, with population and ethnicity-specific waist circumference thresholds and no insulin measurement.[19] Diabetes mellitus is defined by glycaemic thresholds rather than by insulin sensitivity.[20] Severe or rapidly progressive androgen excess in women requires structured biochemical and imaging evaluation before it is attributed to a severe insulin resistance syndrome.[21]
| Condition | Shared features | Distinguishing features |
|---|---|---|
| Metabolic syndrome | Central obesity, raised triglycerides, low HDL cholesterol, raised blood pressure, raised fasting glucose | A defined diagnostic construct requiring three of five harmonised criteria, with ethnicity-specific waist circumference thresholds; insulin measurement is not part of the definition.[19] |
| Type 2 diabetes mellitus | Insulin resistance, hyperinsulinemia, obesity | Defined by glycaemic thresholds (fasting plasma glucose, 2-hour value on oral glucose tolerance test, or HbA1c); insulin resistance alone does not meet diagnostic criteria.[20] |
| Type 1 diabetes mellitus | Hyperglycemia | Autoimmune beta cell destruction with islet autoantibodies and low C-peptide; typically lean; ketoacidosis at presentation.[20] |
| Maturity onset diabetes of the young | Young-onset non-autoimmune hyperglycemia | Autosomal dominant family history over several generations; absent obesity and absent acanthosis nigricans; insulin sensitivity is preserved.[20] |
| Polycystic ovary syndrome | Insulin resistance, acanthosis nigricans, central adiposity, hyperandrogenism | Requires ovulatory dysfunction plus clinical or biochemical hyperandrogenism, with anti-Müllerian hormone or ultrasound morphology as an alternative criterion in adults.[16] |
| Cushing's syndrome | Central adiposity, dysglycemia, hypertension, dyslipidemia | Proximal myopathy, wide violaceous striae, easy bruising, facial plethora; confirmed by failure of cortisol suppression, raised late-night salivary cortisol or raised urinary free cortisol.[15] |
| Acromegaly | Insulin resistance, dysglycemia, acanthosis nigricans, skin tags | Acral enlargement, prognathism, sweating, headache and visual field loss; raised insulin-like growth factor 1 with failure of growth hormone suppression after glucose load. |
| Lipodystrophy syndromes | Extreme insulin resistance, hypertriglyceridemia, hepatic steatosis, acanthosis nigricans | Regional or generalised loss of subcutaneous fat with muscular appearance and prominent veins; low leptin; often a specific genetic diagnosis. Oral estrogen is contraindicated.[11] |
| Type A insulin resistance and related INSR defects | Severe insulin resistance, acanthosis nigricans, hyperandrogenism | Lean habitus, onset in childhood or adolescence, disproportionately severe resistance for the degree of adiposity, and relative preservation of HDL cholesterol with lower triglycerides than in lipodystrophy.[10][21] |
| Type B insulin resistance | Extreme insulin resistance, severe acanthosis nigricans, hyperandrogenism | Abrupt onset, hypercatabolism and weight loss, fluctuation between hyperglycemia and hypoglycemia, very large exogenous insulin requirements, and detectable insulin receptor autoantibodies, usually with coexisting autoimmune disease.[12] |
| Metabolic dysfunction-associated steatotic liver disease | Hepatic steatosis, insulin resistance, dyslipidemia | A hepatic diagnosis requiring imaging or histological steatosis plus at least one of five cardiometabolic criteria; alcohol intake defines the separate MetALD category.[18] |
Epidemiology and Demographics
No single prevalence figure for insulin resistance is meaningful, because there is no accepted diagnostic threshold and because surrogate indices have limited precision. The homeostasis model assessment, for example, has reported coefficients of variation of 31% for the insulin resistance estimate and 32% for the beta cell deficit estimate, which constrains its use for individual classification.[3] Prevalence is therefore reported using defined surrogate conditions.
- Metabolic syndrome is diagnosed when three of five harmonised criteria are met. Waist circumference thresholds are national or regional rather than universal, so measured prevalence differs substantially between populations for reasons of definition as well as biology.[19]
- Prediabetes and type 2 diabetes mellitus are defined by glycaemic thresholds and provide the most consistently comparable population estimates.[20]
- Metabolic dysfunction-associated steatotic liver disease is now defined by hepatic steatosis plus at least one cardiometabolic risk factor, which makes it in effect a hepatic marker of the insulin-resistant state.[18]
Determinants of the distribution of insulin resistance include the following.
- Adiposity distribution and ethnicity. Because central adiposity thresholds are ethnicity-specific, an equivalent degree of insulin resistance occurs at lower body mass index and waist circumference in South Asian and East Asian populations than in populations of European ancestry.[19]
- Genetic background. At least 53 genomic regions are associated with insulin resistance phenotypes, acting largely through reduced peripheral adipose storage capacity.[7]
- Sex. In the Diabetes Prevention Program Outcomes Study, the aggregate microvascular outcome at the end of the study among women was 8.7% (95% CI 7.4-10.2) in the lifestyle group compared with 11.0% (9.6-12.6) in the placebo group and 11.2% (9.7-12.9) in the metformin group, corresponding to reductions of 21% versus placebo (p=0.03) and 22% versus metformin (p=0.02), with no comparable difference in the total cohort.[22]
- Age and life stage. Insulin sensitivity falls transiently during puberty and during the later stages of pregnancy, and declines with age in association with changes in body composition.
Risk Factors
- Excess adiposity, particularly visceral and hepatic fat, and any state in which peripheral subcutaneous adipose expansion is constrained[6][7]
- Physical inactivity and sedentary behaviour[23]
- Family history of type 2 diabetes mellitus and the associated polygenic burden[7]
- Prior gestational diabetes and polycystic ovary syndrome[24][16]
- Short or fragmented sleep and obstructive sleep apnea[14]
- Metabolic dysfunction-associated steatotic liver disease[18]
- Drug exposures, including glucocorticoids, atypical antipsychotic agents and antiretroviral therapy; statin therapy carries a small increase in incident diabetes[17]
- Ethnicity, with lower adiposity thresholds for equivalent risk in several populations[19]
Screening
Screening is directed at dysglycemia and at the associated cardiometabolic conditions rather than at insulin resistance itself, because no insulin-based index has an accepted diagnostic cut-point for individual clinical use.[3][20]
- Dysglycemia. Adults with overweight or obesity and one or more additional risk factors should be tested for prediabetes and type 2 diabetes mellitus, as should all adults from middle adulthood; testing should be repeated at intervals of no more than three years if results are normal, and more frequently if risk factors accumulate.[20][24]
- Cardiovascular risk factors. Blood pressure, fasting lipid profile and waist circumference should be assessed and reassessed periodically.[25]
- Liver disease. People with insulin resistance, prediabetes or type 2 diabetes mellitus should be assessed for metabolic dysfunction-associated steatotic liver disease and risk-stratified for advanced fibrosis using a non-invasive score such as FIB-4, with onward testing where risk is not low.[26][27]
- Polycystic ovary syndrome. All women with the diagnosis should be offered assessment of glycaemic status and of cardiovascular risk factors irrespective of body mass index, with reassessment at least every one to three years.[16]
Natural History, Complications and Prognosis
Natural history
Insulin resistance typically precedes dysglycemia by years. During the compensated phase, glucose tolerance is maintained by increased insulin secretion, and the only detectable abnormalities may be hyperinsulinemia, raised triglycerides and low HDL cholesterol. Progression to impaired glucose tolerance and then to type 2 diabetes mellitus occurs when beta cell compensation fails.[4][13]
In the Diabetes Prevention Program Outcomes Study, over a mean follow-up of 15 years, diabetes incidence was reduced by 27% in the lifestyle intervention group (hazard ratio 0.73, 95% CI 0.65-0.83; p<0.0001) and by 18% in the metformin group (0.82, 0.72-0.93; p=0.001) compared with placebo. At year 15 the cumulative incidences of diabetes were 55% in the lifestyle group, 56% in the metformin group and 62% in the placebo group.[22]
Complications
| System | Complication |
|---|---|
| Metabolic | Prediabetes, type 2 diabetes mellitus, metabolic syndrome, atherogenic dyslipidemia with raised triglycerides and low HDL cholesterol[4][19] |
| Hepatic | Metabolic dysfunction-associated steatotic liver disease, steatohepatitis, hepatic fibrosis, cirrhosis and hepatocellular carcinoma[18][27] |
| Cardiovascular | Hypertension, atherosclerosis, myocardial infarction, stroke, heart failure[25][4] |
| Renal | Chronic kidney disease and diabetic nephropathy, with the highest risk in the severe insulin-resistant diabetes subgroup[8] |
| Reproductive | Polycystic ovary syndrome, ovulatory dysfunction, infertility, adverse pregnancy outcomes[16] |
| Cutaneous | Acanthosis nigricans, skin tags, hirsutism[10] |
| Respiratory | Obstructive sleep apnea[26] |
Prognosis
Prognosis depends principally on whether progression to type 2 diabetes mellitus and cardiovascular disease occurs, and both are modifiable. In the 30-year follow-up of the Da Qing Diabetes Prevention Outcome Study, participants with impaired glucose tolerance who received lifestyle intervention had a median delay in diabetes onset of 3.96 years (95% CI 1.25 to 6.67; p=0.0042), fewer cardiovascular disease events (hazard ratio 0.74, 95% CI 0.59-0.92; p=0.0060), a lower incidence of microvascular complications (0.65, 0.45-0.95; p=0.025), fewer cardiovascular deaths (0.67, 0.48-0.94; p=0.022), fewer all-cause deaths (0.74, 0.61-0.89; p=0.0015), and an average increase in life expectancy of 1.44 years (95% CI 0.20-2.68; p=0.023).[28] In the Diabetes Prevention Program Outcomes Study, participants who did not develop diabetes had a 28% lower prevalence of microvascular complications than those who did (relative risk 0.72, 95% CI 0.63-0.83; p<0.0001).[22]
Diagnosis
History and Symptoms | Physical Examination | Laboratory Findings | CT | MRI | Ultrasound | Other Imaging Findings | Other Diagnostic Studies
History and Symptoms
Insulin resistance is usually asymptomatic. The history should record weight trajectory, dietary pattern, physical activity, sleep duration and quality, symptoms of obstructive sleep apnea, menstrual and reproductive history, family history of type 2 diabetes mellitus and premature cardiovascular disease, and a complete drug history including glucocorticoids, antipsychotic agents and antiretroviral therapy.[26][17] Abrupt onset of severe hyperglycemia with weight loss, or fluctuation between hyperglycemia and hypoglycemia, should raise suspicion of type B insulin resistance.[12]
Physical Examination
- Body mass index, waist circumference and blood pressure
- Acanthosis nigricans of the neck, axillae and groin, and skin tags
- Hirsutism, acne, androgenic alopecia and, in severe cases, clitoromegaly or other virilisation, which should prompt evaluation for a severe insulin resistance syndrome or an androgen-secreting tumour[21]
- Body fat distribution: loss of subcutaneous fat from the limbs and gluteal region with muscular appearance and prominent superficial veins suggests lipodystrophy[11]
- Hepatomegaly, eruptive xanthoma and lipaemia retinalis in severe hypertriglyceridemia
- Features of Cushing's syndrome or acromegaly where a secondary endocrine cause is suspected[15]
Laboratory Findings
Initial testing is directed at glycaemic status and the associated metabolic abnormalities: fasting plasma glucose, HbA1c, and where indicated a 75 g oral glucose tolerance test; fasting lipid profile; liver function tests with calculation of FIB-4; and serum creatinine with urine albumin-to-creatinine ratio.[20][26] Where a severe insulin resistance syndrome is suspected, additional testing includes fasting insulin and C-peptide, leptin, total and free testosterone with sex hormone binding globulin, adiponectin, insulin receptor autoantibodies, and targeted genetic testing.[10][11][12]
Quantification of Insulin Sensitivity
Direct measurement is a research procedure. No index below has a validated universal threshold for clinical diagnosis, and results are not comparable between laboratories because insulin assays are not standardised. Surrogates in common research use are derived from the oral glucose tolerance test,[29] from fasting glucose and insulin,[30] and from fasting triglycerides and glucose.[31]
| Method | Basis | Performance and limitations |
|---|---|---|
| Hyperinsulinemic euglycemic clamp | Insulin is infused to a fixed steady-state concentration while glucose is infused at a variable rate to hold plasma glucose at basal levels; the glucose infusion rate equals whole-body glucose uptake | Reference standard. Labour intensive, requires venous access and frequent sampling, and is confined to research settings.[2] |
| Hyperglycaemic clamp | Plasma glucose is raised acutely by 125 mg/dl above basal and held there by variable glucose infusion, allowing the biphasic insulin response to be characterised | Measures beta cell sensitivity to glucose rather than tissue insulin sensitivity.[2] |
| HOMA-IR | Computer-solved model applied to paired fasting glucose and insulin | Correlated with the euglycemic clamp at Rs=0.88 (p<0.0001), with fasting insulin at Rs=0.81 (p<0.0001) and with the hyperglycaemic clamp at Rs=0.69 (p<0.01). Precision is limited, with coefficients of variation of 31% for insulin resistance and 32% for the beta-cell deficit.[3] |
| Matsuda index | Composite index derived from glucose and insulin values across a 75 g oral glucose tolerance test | Reflects combined hepatic and peripheral sensitivity and requires a full multi-sample OGTT.[29] |
| QUICKI | Reciprocal of the sum of the logarithms of fasting insulin and fasting glucose | A transformation of the same fasting inputs as HOMA-IR and subject to the same assay-dependence.[30] |
| Triglyceride-glucose (TyG) index | Natural logarithm of fasting triglycerides in mg/dl multiplied by fasting glucose in mg/dl, divided by 2 | Against the euglycemic-hyperinsulinemic clamp, Pearson correlation with glucose metabolism rates was -0.681 (p<0.005); the best cut-off value was 4.68, with sensitivity 96.5% and specificity 85.0% (area under the curve 0.858). Requires no insulin assay.[31] |
Imaging Findings
Ultrasound is the usual first-line test for hepatic steatosis; computed tomography and magnetic resonance imaging can quantify visceral and hepatic fat, and magnetic resonance proton density fat fraction and elastography are used for quantification and fibrosis assessment in specialist practice.[27] Imaging also has a role in confirming regional fat loss in suspected lipodystrophy.[11]
Diagnostic Approach
| Clinical suspicion: central obesity, acanthosis nigricans, hypertriglyceridemia with low HDL cholesterol, polycystic ovary syndrome or hepatic steatosis | |||||||||||||
| Baseline evaluation: fasting plasma glucose and HbA1c (with 75 g oral glucose tolerance test if indicated), fasting lipid profile, liver function tests with FIB-4, blood pressure, waist circumference | |||||||||||||
| Typical phenotype: overweight or obesity, adult onset, positive family history | Atypical phenotype: lean or lipoatrophic habitus, childhood onset, virilisation, extreme hypertriglyceridemia, very large insulin requirement | ||||||||||||
| Diagnosis is clinical and no confirmatory index of insulin sensitivity is required. Stratify cardiometabolic risk and treat the associated conditions | Measure fasting insulin and C-peptide, leptin, androgens and insulin receptor autoantibodies; consider genetic testing and refer to a specialist centre | ||||||||||||
Treatment
Medical Therapy | Surgery | Primary Prevention | Secondary Prevention | Cost-Effectiveness of Therapy | Future or Investigational Therapies
Initial Management
Structured lifestyle intervention is the foundation of treatment and has the strongest outcome evidence of any intervention in this condition.
- In the Diabetes Prevention Program, an intensive lifestyle intervention targeting at least 7% weight loss and at least 150 minutes of moderate physical activity per week reduced the incidence of type 2 diabetes mellitus by 58% compared with placebo, while metformin reduced it by 31%.[32]
- The Finnish Diabetes Prevention Study produced a comparable reduction in individuals with impaired glucose tolerance, and the benefit was proportional to the number of lifestyle targets achieved.[33]
- Benefits persist long after the intervention period, with reductions in cardiovascular events, microvascular complications, cardiovascular and all-cause mortality, and a gain in life expectancy at 30 years.[28]
Medical nutrition therapy should emphasise total energy reduction and dietary quality rather than a single macronutrient pattern, combined with at least 150 minutes per week of moderate-intensity aerobic activity, resistance training on two or more days per week, reduction of sedentary time, and attention to sleep duration and to obstructive sleep apnea.[23][14]
Medical Therapy
No agent is licensed to treat insulin resistance as such. Pharmacotherapy is directed at adiposity, dysglycemia and cardiovascular risk.
Metformin reduces hepatic glucose production predominantly through AMP-activated protein kinase-dependent and independent inhibition of gluconeogenesis and mitochondrial complex I.[34] Pioglitazone has been evaluated for diabetes prevention in impaired glucose tolerance,[35] for secondary prevention after ischaemic stroke or transient ischemic attack in insulin-resistant patients without diabetes,[36] and in steatohepatitis with prediabetes or type 2 diabetes mellitus.[37] Incretin-based agents act indirectly through weight reduction, including once-weekly semaglutide in obesity without diabetes,[38] its cardiovascular outcome trial,[39] and tirzepatide.[40] In established diabetes, agent selection follows consensus recommendations based on comorbidity.[41][42]
| Agent or class | Role and supporting evidence |
|---|---|
| Metformin | Reduces hepatic glucose production.[34] Reduced diabetes incidence by 31% in the Diabetes Prevention Program and by 18% over 15 years in its outcomes study,[32][22] and may be considered for prevention in selected high-risk adults.[24] |
| Thiazolidinediones | The only class acting primarily as an insulin sensitiser, through PPAR gamma-mediated redistribution of lipid into subcutaneous adipose tissue. Pioglitazone reduced conversion from impaired glucose tolerance to diabetes,[35] reduced recurrent stroke and myocardial infarction in insulin-resistant patients without diabetes,[36] and improved steatohepatitis.[37] Weight gain, fluid retention, heart failure and fracture risk limit use. |
| GLP-1 receptor agonists | Improve insulin sensitivity indirectly through substantial weight reduction.[38] Once-weekly semaglutide reduced major adverse cardiovascular events in adults with overweight or obesity and established cardiovascular disease but without diabetes.[39] |
| Dual GIP and GLP-1 receptor agonists | Tirzepatide produced dose-dependent and substantial weight reduction in adults with obesity.[40] |
| Glucose-lowering therapy in established diabetes | Choice of agent should be guided by cardiovascular, renal and weight-related comorbidity rather than by glycaemic efficacy alone.[41][42] |
Procedural / Surgical Therapy
Metabolic and bariatric surgery produces the largest and most durable improvement in insulin sensitivity of any available intervention.
- In the STAMPEDE trial, surgical treatment plus medical therapy was superior to intensive medical therapy alone for glycaemic control in patients with type 2 diabetes mellitus and obesity at five years.[43]
- Current indications, which supersede the 1991 National Institutes of Health criteria, recommend surgery for individuals with body mass index of 35 kg/m2 or more regardless of the presence or severity of comorbidity, and for those with body mass index of 30 to 34.9 kg/m2 with metabolic disease. Lower thresholds apply in Asian populations, in whom body mass index above 25 kg/m2 may correspond to clinical obesity.[44]
Long-Term Management
- Weight-loss maintenance is the principal determinant of durable improvement, and requires ongoing behavioural support rather than a time-limited programme.[23][42]
- Periodic reassessment of glycaemic status is required indefinitely, since more than half of high-risk individuals develop diabetes within 15 years even with intervention.[22]
- Cardiovascular risk factors should be treated to target. Weight loss achieved by intensive lifestyle intervention alone did not reduce cardiovascular events in the Look AHEAD trial of patients with established type 2 diabetes mellitus, which supports concurrent pharmacological management of blood pressure and lipids rather than reliance on lifestyle change alone for cardiovascular protection.[45][25]
- Statin therapy should not be withheld because of the small associated increase in incident diabetes, which is outweighed by cardiovascular benefit in patients at moderate or high risk.[17]
- Hepatic risk should be re-stratified periodically with non-invasive fibrosis scores.[27][26]
Special Populations
- Polycystic ovary syndrome. Lifestyle intervention is first line for metabolic and reproductive features. Combined oral contraceptives are first line for irregular cycles and clinical hyperandrogenism, with metformin added or used alone where metabolic features predominate, and letrozole as first-line ovulation induction.[16]
- Lipodystrophy syndromes. Diet is central to management of metabolic complications. Metreleptin is effective for metabolic complications in hypoleptinaemic patients with generalised lipodystrophy and in selected patients with partial lipodystrophy; metformin, statins and fibrates are used as in other patients, and oral estrogen is contraindicated.[11]
- Type B insulin resistance. A standardised protocol of rituximab, cyclophosphamide and pulse corticosteroids induced remission in all seven treated patients at the National Institutes of Health, with normalisation of HbA1c, discontinuation of insulin therapy and resolution of hyperandrogenism; remission was achieved on average 8 months from initiation of treatment.[12]
- Genetic syndromes of severe insulin resistance. Management should be tailored to the specific molecular diagnosis, since receptor defects and lipodystrophies differ in complication profile and in response to therapy; these patients should be managed in specialist centres.[10]
- Severe androgen excess in women. Rapid-onset virilisation warrants structured biochemical and imaging evaluation to exclude an adrenal or ovarian neoplasm before attribution to a severe insulin resistance syndrome.[21]
- Secondary endocrine causes. Where Cushing's syndrome or Cushing's disease is identified, insulin resistance improves with definitive treatment of the underlying hypercortisolism.[15]
- Pregnancy. Physiological insulin resistance increases in the later trimesters; screening and management follow gestational diabetes pathways, and prior gestational diabetes is an indication for lifelong periodic glycaemic screening.[24]
Case Studies
Related Chapters
- Chronic Somogyi rebound
- Metabolic syndrome
- Type 2 diabetes mellitus
- Prediabetes
- Obesity
- Polycystic ovary syndrome
- Metabolic dysfunction-associated steatotic liver disease
- Lipodystrophy
- Acanthosis nigricans
- Metformin
- Thiazolidinedione
- Bariatric surgery
References
- ↑ 1.0 1.1 Randle PJ, Garland PB, Hales CN, Newsholme EA (April 1963). "The glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus". Lancet. 1 (7285): 785–9. doi:10.1016/s0140-6736(63)91500-9. PMID 13990765.
- ↑ 2.0 2.1 2.2 DeFronzo RA, Tobin JD, Andres R (September 1979). "Glucose clamp technique: a method for quantifying insulin secretion and resistance". Am J Physiol. 237 (3): E214–23. doi:10.1152/ajpendo.1979.237.3.E214. PMID 382871.
- ↑ 3.0 3.1 3.2 3.3 Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC (July 1985). "Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man". Diabetologia. 28 (7): 412–9. doi:10.1007/BF00280883. PMID 3899825.
- ↑ 4.0 4.1 4.2 4.3 4.4 Reaven GM (December 1988). "Banting lecture 1988. Role of insulin resistance in human disease". Diabetes. 37 (12): 1595–607. doi:10.2337/diab.37.12.1595. PMID 3056758.
- ↑ 5.0 5.1 Hotamisligil GS, Shargill NS, Spiegelman BM (January 1993). "Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance". Science. 259 (5091): 87–91. doi:10.1126/science.7678183. PMID 7678183.
- ↑ 6.0 6.1 6.2 6.3 Shulman GI (September 2014). "Ectopic fat in insulin resistance, dyslipidemia, and cardiometabolic disease". N Engl J Med. 371 (12): 1131–41. doi:10.1056/NEJMra1011035. PMID 25229917.
- ↑ 7.0 7.1 7.2 7.3 7.4 7.5 Lotta LA, Gulati P, Day FR, Payne F, Ongen H, Savage DB, Langenberg C, O'Rahilly S, Scott RA (January 2017). "Integrative genomic analysis implicates limited peripheral adipose storage capacity in the pathogenesis of human insulin resistance". Nat Genet. 49 (1): 17–26. doi:10.1038/ng.3714. PMID 27841877.
- ↑ 8.0 8.1 8.2 Ahlqvist E, Storm P, Käräjämäki A, Martinell M, Dorkhan M (May 2018). "Novel subgroups of adult-onset diabetes and their association with outcomes: a data-driven cluster analysis of six variables". Lancet Diabetes Endocrinol. 6 (5): 361–369. doi:10.1016/S2213-8587(18)30051-2. PMID 29503172.
- ↑ 9.0 9.1 Wagner R, Heni M, Tabák AG, Machann J, Schick F (January 2021). "Pathophysiology-based subphenotyping of individuals at elevated risk for type 2 diabetes". Nat Med. 27 (1): 49–57. doi:10.1038/s41591-020-1116-9. PMID 33398163 Check
|pmid=value (help). - ↑ 10.0 10.1 10.2 10.3 10.4 10.5 10.6 10.7 Semple RK, Savage DB, Cochran EK, Gorden P, O'Rahilly S (August 2011). "Genetic syndromes of severe insulin resistance". Endocr Rev. 32 (4): 498–514. doi:10.1210/er.2010-0020. PMID 21536711.
- ↑ 11.0 11.1 11.2 11.3 11.4 11.5 11.6 11.7 Brown RJ, Araujo-Vilar D, Cheung PT, Dunger D, Garg A (December 2016). "The Diagnosis and Management of Lipodystrophy Syndromes: A Multi-Society Practice Guideline". J Clin Endocrinol Metab. 101 (12): 4500–4511. doi:10.1210/jc.2016-2466. PMID 27710244.
- ↑ 12.0 12.1 12.2 12.3 12.4 12.5 12.6 Malek R, Chong AY, Lupsa BC, Lungu AO, Cochran EK, Gorden P (August 2010). "Treatment of type B insulin resistance: a novel approach to reduce insulin receptor autoantibodies". J Clin Endocrinol Metab. 95 (8): 3641–7. doi:10.1210/jc.2010-0167. PMID 20484479.
- ↑ 13.0 13.1 13.2 13.3 13.4 Petersen MC, Shulman GI (October 2018). "Mechanisms of Insulin Action and Insulin Resistance". Physiol Rev. 98 (4): 2133–2223. doi:10.1152/physrev.00063.2017. PMID 30067154.
- ↑ 14.0 14.1 14.2 14.3 Broussard JL, Ehrmann DA, Van Cauter E, Tasali E, Brady MJ (October 2012). "Sleep restriction reduces adipose tissue insulin sensitivity in healthy subjects". Ann Intern Med. 157 (8): 549–57. doi:10.7326/0003-4819-157-8-201210160-00005. PMID 23070488.
- ↑ 15.0 15.1 15.2 15.3 15.4 Fleseriu M, Auchus R, Bancos I, Ben-Shlomo A, Bertherat J (December 2021). "Consensus on diagnosis and management of Cushing's disease: a guideline update". Lancet Diabetes Endocrinol. 9 (12): 847–875. doi:10.1016/S2213-8587(21)00235-7. PMID 34687601 Check
|pmid=value (help). - ↑ 16.0 16.1 16.2 16.3 16.4 16.5 16.6 Teede HJ, Tay CT, Laven J, Dokras A, Moran LJ, Piltonen TT (September 2023). "Recommendations From the 2023 International Evidence-based Guideline for the Assessment and Management of Polycystic Ovary Syndrome". J Clin Endocrinol Metab. 108 (10): 2447–2469. doi:10.1210/clinem/dgad463. PMID 37580314 Check
|pmid=value (help). Vancouver style error: initials (help) - ↑ 17.0 17.1 17.2 17.3 17.4 Sattar N, Preiss D, Murray HM, Welsh P, Buckley BM (February 2010). "Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials". Lancet. 375 (9716): 735–42. doi:10.1016/S0140-6736(09)61965-6. PMID 20167359.
- ↑ 18.0 18.1 18.2 18.3 18.4 18.5 Rinella ME, Lazarus JV, Ratziu V, Francque SM, Sanyal AJ, Kanwal F (December 2023). "A multisociety Delphi consensus statement on new fatty liver disease nomenclature". Hepatology. 78 (6): 1966–1986. doi:10.1097/HEP.0000000000000520. PMID 37363821 Check
|pmid=value (help). - ↑ 19.0 19.1 19.2 19.3 19.4 19.5 Alberti KG, Eckel RH, Grundy SM, Zimmet PZ, Cleeman JI, Donato KA, Fruchart JC, James WP, Loria CM, Smith SC (October 2009). "Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity". Circulation. 120 (16): 1640–5. doi:10.1161/CIRCULATIONAHA.109.192644. PMID 19805654.
- ↑ 20.0 20.1 20.2 20.3 20.4 20.5 20.6 20.7 American Diabetes Association Professional Practice Committee (January 2026). "2. Diagnosis and Classification of Diabetes: Standards of Care in Diabetes-2026". Diabetes Care. 49 (Suppl 1): S27–S49. doi:10.2337/dc26-S002. PMID 41358893 Check
|pmid=value (help). - ↑ 21.0 21.1 21.2 21.3 Elhassan YS, Hawley JM, Cussen L, Abbara A, Clarke SA (October 2025). "Society for Endocrinology Clinical Practice Guideline for the Evaluation of Androgen Excess in Women". Clin Endocrinol (Oxf). 103 (4): 540–566. doi:10.1111/cen.15265. PMID 40364581 Check
|pmid=value (help). - ↑ 22.0 22.1 22.2 22.3 22.4 Diabetes Prevention Program Research Group (November 2015). "Long-term effects of lifestyle intervention or metformin on diabetes development and microvascular complications over 15-year follow-up: the Diabetes Prevention Program Outcomes Study". Lancet Diabetes Endocrinol. 3 (11): 866–75. doi:10.1016/S2213-8587(15)00291-0. PMID 26377054.
- ↑ 23.0 23.1 23.2 American Diabetes Association Professional Practice Committee (January 2026). "5. Facilitating Positive Health Behaviors and Well-being to Improve Health Outcomes: Standards of Care in Diabetes-2026". Diabetes Care. 49 (Suppl 1): S89–S131. doi:10.2337/dc26-S005. PMID 41358898 Check
|pmid=value (help). - ↑ 24.0 24.1 24.2 24.3 American Diabetes Association Professional Practice Committee (January 2026). "3. Prevention or Delay of Diabetes and Associated Comorbidities: Standards of Care in Diabetes-2026". Diabetes Care. 49 (Suppl 1): S50–S60. doi:10.2337/dc26-S003. PMID 41358891 Check
|pmid=value (help). - ↑ 25.0 25.1 25.2 American Diabetes Association Professional Practice Committee (January 2026). "10. Cardiovascular Disease and Risk Management: Standards of Care in Diabetes-2026". Diabetes Care. 49 (Suppl 1): S216–S245. doi:10.2337/dc26-S010. PMID 41358899 Check
|pmid=value (help). - ↑ 26.0 26.1 26.2 26.3 26.4 American Diabetes Association Professional Practice Committee (January 2026). "4. Comprehensive Medical Evaluation and Assessment of Comorbidities: Standards of Care in Diabetes-2026". Diabetes Care. 49 (Suppl 1): S61–S88. doi:10.2337/dc26-S004. PMID 41358897 Check
|pmid=value (help). - ↑ 27.0 27.1 27.2 27.3 Rinella ME, Neuschwander-Tetri BA, Siddiqui MS, Abdelmalek MF, Caldwell S (May 2023). "AASLD Practice Guidance on the clinical assessment and management of nonalcoholic fatty liver disease". Hepatology. 77 (5): 1797–1835. PMID 36727674 Check
|pmid=value (help). - ↑ 28.0 28.1 Gong Q, Zhang P, Wang J, Ma J, An Y (June 2019). "Morbidity and mortality after lifestyle intervention for people with impaired glucose tolerance: 30-year results of the Da Qing Diabetes Prevention Outcome Study". Lancet Diabetes Endocrinol. 7 (6): 452–461. doi:10.1016/S2213-8587(19)30093-2. PMID 31036503.
- ↑ 29.0 29.1 Matsuda M, DeFronzo RA (September 1999). "Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison with the euglycemic insulin clamp". Diabetes Care. 22 (9): 1462–70. doi:10.2337/diacare.22.9.1462. PMID 10480510.
- ↑ 30.0 30.1 Katz A, Nambi SS, Mather K, Baron AD, Quon MJ (July 2000). "Quantitative insulin sensitivity check index: a simple, accurate method for assessing insulin sensitivity in humans". J Clin Endocrinol Metab. 85 (7): 2402–10. PMID 10902785.
- ↑ 31.0 31.1 Guerrero-Romero F, Simental-Mendía LE, González-Ortiz M, Martínez-Abundis E, Ramos-Zavala MG (July 2010). "The product of triglycerides and glucose, a simple measure of insulin sensitivity. Comparison with the euglycemic-hyperinsulinemic clamp". J Clin Endocrinol Metab. 95 (7): 3347–51. doi:10.1210/jc.2010-0288. PMID 20484475.
- ↑ 32.0 32.1 Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, Nathan DM (February 2002). "Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin". N Engl J Med. 346 (6): 393–403. doi:10.1056/NEJMoa012512. PMID 11832527.
- ↑ Tuomilehto J, Lindström J, Eriksson JG, Valle TT, Hämäläinen H (May 2001). "Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance". N Engl J Med. 344 (18): 1343–50. doi:10.1056/NEJM200105033441801. PMID 11333990.
- ↑ 34.0 34.1 Rena G, Hardie DG, Pearson ER (September 2017). "The mechanisms of action of metformin". Diabetologia. 60 (9): 1577–1585. doi:10.1007/s00125-017-4342-z. PMID 28776086.
- ↑ 35.0 35.1 DeFronzo RA, Tripathy D, Schwenke DC, Banerji M, Bray GA (March 2011). "Pioglitazone for diabetes prevention in impaired glucose tolerance". N Engl J Med. 364 (12): 1104–15. doi:10.1056/NEJMoa1010949. PMID 21428766.
- ↑ 36.0 36.1 Kernan WN, Viscoli CM, Furie KL, Young LH, Inzucchi SE (April 2016). "Pioglitazone after ischemic stroke or transient ischemic attack". N Engl J Med. 374 (14): 1321–31. doi:10.1056/NEJMoa1506930. PMID 26886418.
- ↑ 37.0 37.1 Cusi K, Orsak B, Bril F, Lomonaco R, Hecht J (September 2016). "Long-term pioglitazone treatment for patients with nonalcoholic steatohepatitis and prediabetes or type 2 diabetes mellitus: a randomized trial". Ann Intern Med. 165 (5): 305–315. doi:10.7326/M15-1774. PMID 27322798.
- ↑ 38.0 38.1 Wilding J, Batterham RL, Calanna S, Davies M, Van Gaal LF (March 2021). "Once-weekly semaglutide in adults with overweight or obesity". N Engl J Med. 384 (11): 989–1002. doi:10.1056/NEJMoa2032183. PMID 33567185 Check
|pmid=value (help). Vancouver style error: initials (help) - ↑ 39.0 39.1 Lincoff AM, Brown-Frandsen K, Colhoun HM, Deanfield J, Emerson SS (December 2023). "Semaglutide and cardiovascular outcomes in obesity without diabetes". N Engl J Med. 389 (24): 2221–2232. doi:10.1056/NEJMoa2307563. PMID 37952131 Check
|pmid=value (help). - ↑ 40.0 40.1 Jastreboff AM, Aronne LJ, Ahmad NN, Wharton S, Connery L (July 2022). "Tirzepatide once weekly for the treatment of obesity". N Engl J Med. 387 (3): 205–216. doi:10.1056/NEJMoa2206038. PMID 35658024 Check
|pmid=value (help). - ↑ 41.0 41.1 Davies MJ, Aroda VR, Collins BS, Gabbay RA, Green J (December 2022). "Management of hyperglycaemia in type 2 diabetes, 2022. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD)". Diabetologia. 65 (12): 1925–1966. doi:10.1007/s00125-022-05787-2. PMID 36151309 Check
|pmid=value (help). - ↑ 42.0 42.1 42.2 American Diabetes Association Professional Practice Committee (January 2026). "8. Obesity and Weight Management for the Prevention and Treatment of Diabetes: Standards of Care in Diabetes-2026". Diabetes Care. 49 (Suppl 1): S166–S182. doi:10.2337/dc26-S008. PMID 41358882 Check
|pmid=value (help). - ↑ Schauer PR, Bhatt DL, Kirwan JP, Wolski K, Aminian A (February 2017). "Bariatric surgery versus intensive medical therapy for diabetes - 5-year outcomes". N Engl J Med. 376 (7): 641–651. doi:10.1056/NEJMoa1600869. PMID 28199805.
- ↑ Eisenberg D, Shikora SA, Aarts E, Aminian A, Angrisani L (December 2022). "2022 American Society for Metabolic and Bariatric Surgery (ASMBS) and International Federation for the Surgery of Obesity and Metabolic Disorders (IFSO): Indications for Metabolic and Bariatric Surgery". Surg Obes Relat Dis. 18 (12): 1345–1356. doi:10.1016/j.soard.2022.08.013. PMID 36280539 Check
|pmid=value (help). - ↑ Look AHEAD Research Group (July 2013). "Cardiovascular effects of intensive lifestyle intervention in type 2 diabetes". N Engl J Med. 369 (2): 145–54. doi:10.1056/NEJMoa1212914. PMID 23796131.