Insulin Resistance – Types, Causes, Symptoms, Treatment

Causes of Insulin Resistance

Insulin resistance etiology can be divided into acquired, hereditary, and mixed. The great majority of people with insulin resistance fall into the acquired categories.

Acquired

• Excess dysfunctional adipose tissue
• Aging
• Physical inactivity
• Nutritional imbalance
• Medications (glucocorticoids, anti-adrenergic, protease inhibitors, atypical antipsychotics, and some exogenous insulin)
• Increased sodium diets
• Glucose toxicity
• Lipotoxicity from excess circulating free fatty acids

In addition to the heritable components of the above etiologies of insulin resistance, there are a number of unrelated genetic syndromes with associated insulin resistance.

Genetic

• Myotonic Dystrophy
• Ataxia-telangiectasia
• Alstom syndrome
• Rabson-Mendenhall syndrome
• Werner syndrome
• Lipodystrophy
• PCOS
• Type-A insulin resistance: Characterized by severe insulin resistance (abnormal glucose homeostasis, ovarian virialization, and acanthosis nigricans) in the absence of anti-insulin antibodies; typically occurs before middle age
• Type-B insulin resistance: Characterized by the development of anti-insulin antibodies (typically in middle age) with resultant abnormal glucose homeostasis, ovarian hyperandrogenism, and acanthosis nigricans

Of note, an alternative classification of insulin resistance is the division for the site of dysfunction concerning the insulin receptor itself as opposed to etiology. The categories include the following:

• Pre-receptor
• Receptor
• Post-receptor

Pathophysiology of Insulin Resistance

The three primary sites of insulin resistance are the muscle, liver, and adipose tissue. Insulin resistance is postulated to begin in muscle tissue with immune-mediated inflammatory change and excess free fatty acids, causing ectopic lipid deposition. [rx][rx]Muscle accounts for up to 70% of glucose disposal. With impaired muscle uptake, excess glucose returns to the liver increasing de novo lipogenesis (DNL) and circulating free fatty acids, further contributing to ectopic fat deposition and insulin resistance

Adipose Tissue

By use of the hyperinsulinemic-euglycemic clamp technique, researchers determined that lipolysis is most sensitive to insulin. Failure of insulin to suppress lipolysis in insulin-resistant adipose tissue, especially visceral adipose tissue, increases circulating free fatty acids. Higher levels of circulating FFAs directly affect both liver and muscle metabolism, further exacerbating insulin resistance.

Muscle Tissue

After intake of a caloric load and conversion to glucose, muscle is the primary site for glucose disposal, accounting for up to 70% of tissue glucose uptake. With excess calorie loads, glucose uptake by muscle exceeds capacity, and excess glucose returns to the liver where it triggers DNL. Increased DNL increases triglyceride and FFA production, causing ectopic fat deposition into the liver, muscle, and adipose tissue. As a result, insulin resistance increases as well as the production of inflammatory markers. Additional factors influencing insulin resistance in muscle tissue include physical inactivity and genetic risk.

Hepatic Tissue

Insulin resistance in muscle results in increased delivery of glucose substrate to the liver, which triggers DNL, with associated inflammation, and ectopic lipid deposition. Insulin resistance in adipose tissue results in increased lipolysis in adipocytes, resulting in increased circulating FFA and further exacerbating steatosis and insulin resistance in muscle tissue. In the presence of caloric intake, insulin reduces hepatic glucose production via inhibition of glycogenolysis, limiting the postprandial rise in glucose. With insulin resistance, this feedback mechanism is impaired, and hepatic glucose production continues to rise, even as postprandial glucose rises. Glucotoxicity, associated with elevated glucose levels, further contributes to insulin resistance.

Diagnosis of Insulin Resistance

The clinical presentation of insulin resistance is variable with respect to both history and physical exam findings. It is dependent on the subset of insulin resistance present, duration of the condition, level of beta-cell function, and the individual’s propensity for the secondary illnesses due to insulin resistance. Common presentations include:

• The asymptomatic patients with obesity, hypertension, or hyperlipidemia
• Those with metabolic syndrome
• Prediabetes or type 2 diabetes mellitus
• Those with symptomatic microvascular disease (retinopathy, neuropathy, or nephropathy)
• Those with macrovascular disease (stroke, PAD, and CAD)
• Those with PCOS
• Those with type A or type B insulin resistance
• Elevated blood pressure
• Gender and race-specific increased waist circumference
• Those with xanthelasma or xanthomas
• The stigmata of PCOS (menstrual irregularities, hirsutism, acne, and alopecia)
• Acanthosis nigricans, a patchy velvety brown pigmentation around the neck axilla and groin regions.
• The stigmata of one of several genetic syndromes that include insulin resistance

Multiple criteria for metabolic syndrome exist. In 2009, a joint scientific statement harmonizing criteria for MetS was released. MetS is identified by the presence of 3 or more of the following diagnostic cut points:

• A waist circumference of 32” to 40” based on gender and race
• Elevated triglycerides greater than or equal to 150 mg/dL
• Reduced HDL less than 40 mg/ dL in men, less than 50 mg/ dL in women
• Elevated blood pressure greater than or equal to 130 mmHg systolic and/or greater than or equal to 85 mmHg diastolic
• Elevated fasting glucose greater than or equal to 100 mg/ dL

The American College of Endocrinology identify specific physiologic abnormalities which increase the risk of Insulin Resistance Syndrome as follows:

• Impaired glucose tolerance or impaired fasting glucose
• Abnormal uric acid metabolism
• Dyslipidemia (increased triglycerides, decreased HDL-C, or small, dense LDL)
• Hemodynamic changes such as elevated blood pressure
• Prothrombic factors (PAI-1, fibrinogen)
• Markers of inflammation (CRP, WBC, etc.)
• Endothelial dysfunction

Other factors include the following:

• Body mass index (BMI) greater than or equal to 25 kg/m2
• Diagnosis of CVD, PCOS, NAFLD, or acanthosis nigricans
• A family history of T2DM, hypertension, or CVD
• Sedentary lifestyle
• Non-Caucasian ethnicity
• Age greater than 40 years

Differential Diagnosis

• Obesity: Excess body weight is categorized as overweight (BMI of 25 to 29.9), class I obesity (BMI of 30 to 34.9), class II obesity (BMI 35.0 to 39.9), and class III obesity (BMI greater than 40)
• Hypertension: The most recent ACC/AHA guidelines for the diagnosis of hypertension include systolic BP greater than or equal to 130 mmHg or diastolic BP greater than or equal to 80 mmHg
• Hypertriglyceridemia: Elevated triglyceride levels (greater than or equal to 150 mg/dL)
• Type 1 diabetes
• Type 2 diabetes
• Glucose intolerance including impaired fasting glucose, impaired glucose tolerance, gestational diabetes, type 1 diabetes, and type 2 diabetes
• Lipodystrophy (acquired, localized or generalized): Loss of adipose tissue that results from either genetic or acquired causation and can result in the ectopic deposition of fat in either hepatic or muscular tissue
• Polycystic Ovary Syndrome (PCOS)

Treatment of Insulin Resistance

Intensive Lifestyle Intervention

Lifestyle intervention represents the cornerstone of treatment for insulin resistance. Dietary intervention should include a combination of calorie restriction and reduction of high glycemic index carbohydrates.[rx][rx][rx] Physical activity improves both calorie expenditure and insulin sensitivity in muscle tissue.

Individuals with insulin resistance are at high risk of developing T2DM. The Diabetes Prevention Program and its Outcomes Study (DPP & DPPOS) demonstrated that lifestyle intervention was both a significant and cost-effective intervention for diabetes prevention in high-risk adults.

• A dietary therapy with sodium reduction, fat reduction, calorie restriction, and attention to the glycemic index of foods
• Education, support, and personalized programs
• A 7% weight loss reduced the onset of T2DM by 58%
• DPP included a metformin arm which reduced the onset of T2DM by 31%

Specific Pharmacological Interventions for Blood Glucose Management

While no medications are FDA approved for the treatment of insulin resistance, general approaches include the following:

• Metformin: This is considered first-line therapy for medication treatment of T2DM and is approved for use in polycystic ovary syndrome. The DPP/DPPO study showed that the addition of metformin and lifestyle interventions combined were medically useful and cost-effective. Despite the concerns of use in mild to moderate renal dysfunction, several organizations including the American Geriatric Society and the KDIGO (Kidney Disease Improving Global Outcomes) guidelines endorse use as long as the GFR is greater than 30.
• Glucagon-like peptide one inhibitors: The GLP-1 receptor agonists stimulate the GLP-1 receptors in the pancreas, thereby increasing insulin release and inhibiting glucagon secretion. Use of GLP-1 agonists is associated with weight loss, which may reduce IR. Liraglutide is FDA approved as and an anti-obesity agent.
• Sodium-glucose cotransporter two inhibitors: The SGLT2 inhibitors increase the excretion of urinary glucose, thereby reducing plasma glucose levels and exogenous insulin requirements. Use of SGLT2 inhibitors has also been associated with weight loss, which may reduce insulin resistance.
• Thiazolidinediones: TZDs improve insulin sensitivity by increasing insulin-dependent glucose disposal in muscle and adipose tissue as well as decreasing hepatic glucose output. Though effective, associated secondary weight gain and fluid retention, with associated cardiovascular concerns, limit their use.
• Dipeptidyl peptidase-4 inhibitors: The DPP-4 inhibitors prolong the activity of endogenous GLP-1 and gastric inhibitory polypeptide(GIP) by preventing their breakdown.

For individuals on insulin therapy:

• The use of concentrated insulin preparations when large doses (greater than 200 units per day) of insulin are required to improve tolerance and absorption. At this time U-500 and U-200 Lispro and U-300 Glargine

Surgery

Surgical intervention in the form of gastric sleeve, banding, and bypass is available for qualified individuals with obesity. The excess fat loss associated with bariatric surgery improves insulin sensitivity. The STAMPEDE trial has shown good evidence of the benefit of bariatric surgery on type 2 diabetes.

Effect of Exercise in Diabetes and Insulin Resistance

Short-Term Effects of Exercise[rx][rx][rx]

Type 2 Diabetes – Exercise leads to an increase in insulin sensitivity. Patients on oral hypoglycemic have decreased blood glucose concentration after exercise. Studies have suggested that patients who were fasting, no change in blood glucose concentrations noted; whereas, blood concentrations decreased in patients who exercised after eating.

Type 1 Diabetes

• Patients with well-controlled diabetes on insulin regimen: Higher serum insulin concertation is noted during exercise due to increased temperature and blood flow leading to increased absorption from subcutaneous depots. Exogenous insulin can’t be shut off. Hence, these patients have a drop in blood glucose levels much larger than in normal individuals.
• Patients with diabetes and poor metabolic control: Exercise causes a paradoxical elevation in blood glucose concentrations

Long-Term Effects of Exercise[rx][rx]

Patients are insulin resistant due to many defects in glucose metabolism.

• Decreased number and function of both insulin receptors and glucose transporters
• Decreased activity of some intracellular enzymes
• Low maximal oxygen uptake during exercise

An exercise program leads to increased activity of mitochondrial enzymes, increased insulin sensitivity, and muscle capillary recruitment. Adding resistance training to aerobic exercise provides an additional benefit of increased insulin sensitivity.

Blood Glucose Management During Exercise

General principles for diabetic patients for exercise regimens:

• Maintain a high level of fluid intake before, during, and after exercise
• Maintaining blood sugar logs before, during, and after exercise
• If blood glucose is less than 100 mg/dL, it is recommended to ingest food, such as glucose tablets, juice. About 15 to 30 grams of quickly absorbed carbohydrate is recommended to be ingested 15 to 30 minutes before exercise. Extra ingestion of food may be warranted during exercise based on blood glucose testing during the exercise.  Immediately after excise slowly absorbed carbohydrates such as dried fruit, granola bars or trail mix are recommended as patients are at risk of late hypoglycemia.
• Vigorous exercise is to be avoided in the presence of substantial hyperglycemia greater than 250 mg/dl.
• Hypoglycemia is not common in patients with type 2 diabetes not treated with insulin or oral hypoglycemics. Ingestion of extra carbohydrates is not required.
• Use insulin about 60 to 90 minutes before exercise to prevent increased insulin absorption along with injecting in a site other than muscle to be exercised. For example, inject into arms when cycling exercise and into the abdomen when the exercise involves both the arms and legs.[rx][rx][rx]