Question

Effects of a Deleted Insulin Receptor A strain of mice specifically lacking the insulin receptor of liver is found to have mild fasting hyperglycemia (blood glucose \(=132 \mathrm{mg} / \mathrm{dL}\), vs. \(101 \mathrm{mg} / \mathrm{dL}\) in controls) and a more striking hyperglycemia in the fed state (glucose \(=363 \mathrm{mg} / \mathrm{dL}\), vs. \(135 \mathrm{mg} / \mathrm{dL}\) in controls). The mice have higher than normal levels of glucose 6-phosphatase in the liver and elevated levels of insulin in the blood. Explain these observations.

Short answer

Lack of liver insulin receptors in mice causes hyperglycemia due to impaired glucose uptake and increased glucose production, despite elevated blood insulin levels.

Step-by-step solution

Understanding the Role of Insulin

Insulin is a hormone that helps control blood glucose levels by facilitating the uptake of glucose into cells, particularly in the liver, muscle, and fat tissue. The presence of insulin receptors on the liver is crucial for this process. Without functional insulin receptors, the liver cannot effectively uptake glucose, leading to elevated blood sugar levels.

Fasting Hyperglycemia Explained

In fasting conditions, the liver usually releases glucose into the bloodstream by glycogenolysis and gluconeogenesis. In mice lacking liver insulin receptors, insulin's ability to suppress these processes is impaired, resulting in higher blood glucose levels during fasting because the liver continues to release glucose unchecked (132 mg/dL vs. 101 mg/dL in controls).

Fed State Hyperglycemia Analyzed

During the fed state, insulin is typically released from the pancreas and promotes glucose uptake by liver cells, storing it as glycogen or utilizing it for fat synthesis. Mice without liver insulin receptors cannot store glucose, so blood glucose levels remain high (363 mg/dL vs. 135 mg/dL in controls), despite the presence of insulin.

Glucose 6-Phosphatase Levels

Glucose 6-phosphatase is an enzyme that converts glucose 6-phosphate to glucose, promoting its release into the bloodstream. The elevated levels of this enzyme in the liver of the affected mice enhance gluconeogenesis and glycogenolysis, contributing to hyperglycemia.

Elevated Blood Insulin Levels

When cells are insulin resistant (as in this case due to lack of hepatic receptors), the pancreas compensates by secreting more insulin in an attempt to reduce blood glucose levels. This leads to elevated insulin levels in the bloodstream of these mice.

Key concepts

Fasting Hyperglycemia

Fasting hyperglycemia is a condition where blood sugar levels remain elevated even after a period of fasting, such as overnight. In normal circumstances, insulin helps to suppress the liver’s glucose production during fasting. However, in the case of mice lacking insulin receptors in the liver, this suppression does not occur, leading to elevated blood glucose levels.

Without functional receptors, insulin is unable to instruct the liver to stop releasing stored glucose. Consequently, the liver continues to produce and release glucose into the bloodstream unchecked. This is why fasting hyperglycemia is particularly evident, as it reflects the liver's inability to regulate glucose output in response to insufficient insulin signaling.

Glucose 6-Phosphatase

Glucose 6-phosphatase is an important enzyme in the liver, responsible for converting glucose 6-phosphate into free glucose, which can then be released into the bloodstream. Increased activity of this enzyme in mice without insulin receptors means the liver releases more glucose, contributing to higher blood sugar levels.

The lack of insulin signaling due to missing receptors can lead to an upregulation of glucose 6-phosphatase. This upregulation further exacerbates the problem, as more glucose is made available for release into the blood, driving hyperglycemia during both fasting and fed states.

Insulin Resistance

Insulin resistance occurs when cells in the body do not respond adequately to insulin, preventing glucose from being efficiently absorbed from the bloodstream. In our specific case, the liver’s inability to respond to insulin due to the absence of insulin receptors leads to a condition akin to selective insulin resistance.

The pancreas responds by secreting more insulin in an attempt to lower blood glucose levels. This agricultural problem of insulin resistance leads to higher insulin levels in the bloodstream, but without the desired effect on liver glucose uptake or storage. This miscommunication between insulin production and receptor response significantly contributes to the altered glucose metabolism seen in these mice.

Gluconeogenesis

Gluconeogenesis is the metabolic process of forming glucose from non-carbohydrate sources, such as lactate, glycerol, and amino acids. It is typically suppressed by insulin after eating, but in mice lacking hepatic insulin receptors, this suppression is reduced.

This leads to an increased conversion of substrates into glucose, even when dietary glucose is available. The elevated gluconeogenesis observed in these mice is a direct result of impaired insulin signaling, promoting glucose production beyond normal metabolic needs, thus contributing to hyperglycemia.

Liver Glucose Metabolism

Liver glucose metabolism involves multiple pathways, including glycogenolysis (breaking down glycogen into glucose) and gluconeogenesis. The liver plays a pivotal role in maintaining blood sugar levels. It responds to insulin by storing glucose as glycogen, but without insulin signaling, these processes become dysregulated.

In the case of mice without liver insulin receptors, the usual metabolic pathways that lower blood glucose are impaired. The liver fails to store glucose appropriately, and instead, processes like gluconeogenesis continue unhindered, leading to persistent hyperglycemia. This imbalance can have widespread effects on overall metabolism, reflecting how critical insulin signaling within the liver is for maintaining normal glucose levels.