How obesity leads to prediabetes?
Clinical Nutrition • • 1 minute to read • By Dr Aakash Bansal, INFS Faculty
Author- Dr Aakash Bansal
Insulin is a hormone released by β-cells of the pancreas which helps to mediate glucose uptake in the target tissues, primarily the liver, muscle, and adipose tissues. Insulin resistance (IR) is defined as an impaired biological response to insulin stimulation of these target tissues. It affects the glucose uptake in the cells, resulting in increased secretion of insulin from β-cells resulting in hyperinsulinemia. If it goes uncontrolled, it can result in various metabolic consequences like hyperglycemia, dyslipidemia, visceral adiposity, hypertension, hyperuricemia.
The major consequence of IR is type 2 diabetes (T2DM). The development of IR leads to a compensatory increase in insulin production which results in weight gain and thus aggravates the issue of insulin resistance. This cycle continues until β-cells can no longer produce enough insulin to cater to the increased demand in the body, resulting in hyperglycemia. With continuously increased demand and affected supply of insulin, glucose levels rise and result in type 2 diabetes.
Causes of Insulin Resistance
These can be divided into two broad categories:
Acquired (a most common one)
- Excess dysfunctional adipose tissue ( visceral and ectopic fat)
- Sedentary Lifestyle
- Excess calorie intake
- Medications (steroids; exogenous insulin)
- Increase sodium (salt) intake
- Myotonic Dystrophy – a genetic disorder causing progressive loss and weakness of muscles
- Rabson-Mendenhall Syndrome – a rare autosomal disorder causing mutations in the insulin receptor gene and thus severe insulin resistance
- Lipodystrophy – a genetic disorder causing abnormal fat distribution in the body
- Type-A IR – severe IR in the absence of anti-insulin antibodies
- Type-B IR – characterized by the development of anti-insulin antibodies
Three primary sites of IR are muscle, liver, and adipose tissue. It is hypothesized that it begins in muscle tissue resulting in inflammatory changes and excess free fatty acids, leading to lipotoxicity and ectopic fat deposition. With impai red intake by muscle tissues, excess glucose returns to the liver resulting in fat production (de-novo lipogenesis - DNL) which increases free fatty acids circulation, further resulting in ectopic fat distribution and increased insulin resistance.
- Adipose tissue
Failure of insulin to suppress lipolysis ( breakdown of lipids) in insulin resistance adipose tissues increase free-flowing fatty acids which affect both liver and muscle tissues, thus aggravating insulin resistance.
- Muscle Tissue
Muscle tissues account for 70% of glucose uptake in the body. Excess calorie intake and a sedentary lifestyle exceed the glucose uptake capacity of muscle tissues and thus excess glucose reaches the liver and initiates DNL. Increased DNL increases free fatty acids in the blood causing ectopic fat distribution into the liver (non-alcoholic fatty liver), muscle, and adipose tissues. This results in IR and the release of inflammatory markers.
- Hepatic (Liver) Tissue
Along with the factors triggering DNL and increased flow of free fatty acids, insulin resistance impairs the mechanism of glycogen breakdown also. Glucose is stored in the liver and muscles as glycogen and it breaks down into glucose and water (by the process of glycogenolysis) when blood sugar levels drop down. In case of excess calorie intake, insulin suppresses the process of glycogenolysis and prevents the postprandial rise of glucose in the blood. With IR, this pathway gets impaired, glycogen breaks down into glucose and water and thus raises postprandial blood glucose levels. Glucotoxicity, along with elevated glucose levels, further aggravates insulin resistance.
- Hyperinsulinemic-euglycemic glucose clamp technique
It’s a research technique in which a fasted, non-diabetic patient is infused with insulin to achieve hyperinsulinemia, and euglycemia is maintained by infusing a 20% dextrose solution. The amount of glucose required to reach a steady-state reflects the external supply of glucose needed to compensate for hyperinsulinemia. IR is then calculated on the basis of whole-body glucose disposal and body size. Being a very complex technique, it has limited usefulness in clinical settings.
It involves triglycerides alone or with HDL cholesterol. Patients with prediabetes and triglycerides > 150 g/dL are more prone to IR.
- Metabolic Syndrome
In 2009, a scientific criterion to assess metabolic syndrome was released. It is identified by the presence of 3 or more of the following features:
- A waist circumference of 32” or 40” based on gender or race
- Triglycerides ≥150 mg/dL
- HDL <40 mg/ dL in men and <50 mg/dL in women
- Blood pressure ≥ 130 mmHg systolic and/or ≥ 85 mmHg diastolic
- Fasting glucose ≥ 100 mg/dL
- Intensive Lifestyle Intervention
It is one of the foundations of management for insulin resistance. It includes calorie restriction and a physically active schedule that helps to increase both calorie expense and insulin sensitivity in muscle tissues. As IR can lead to Type 2 diabetes, The Diabetes Prevention Program and its Outcome Study (DPP and DPPOS) have advised that lifestyle intervention is both a significant and cost-effective intervention for diabetes prevention:
Reduction in sodium intake and saturated fats
- Calorie restriction
- 7% weight loss that reduces the onset of type 2 diabetes by 58%
Always under the physician's guidance
Major complications are related to micro and macrovascular complications. It can lead to damage of the kidney (nephropathy), damage of the eye (retinopathy), or damage of peripheral nerves (neuropathy). Macrovascular disease secondary to IR can cause pulmonary artery disease, coronary artery disease, or cardiovascular disorder.
Primary intervention in IR needs public education regarding the significance of regular health monitoring and maintaining a healthy diet and increased activity levels that keep the weight under check which will reduce the risk of IR, metabolic syndrome, and thus type 2 diabetes along with associated complications.
- Freeman, A.M. and Pennings, N. (2019). Insulin Resistance. [online] Nih.gov.
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