Hepatic insulin resistance

Hepatic insulin resistance

What is Hepatic insulin resistance?

The liver is a vital organ in vertebrates that is responsible for coordinating the entire body's metabolism. The liver cells, or hepatocytes, perform the various functions of the liver. Some of the major functions of the liver include gluconeogenesis, glycogenolysis, glycogenesis, lipogenesis, cholesterol synthesis, coagulating factor synthesis such as fibrinogen, converting ammonia to urea, bile production and excretion, plasma protein synthesis, and the production of inflammatory proteins such as C-reactive protein (CRP). Many of these hepatic functions are tightly controlled by circulating hormones like insulin.

Insulin is a hormone that affects the entire body's metabolism. It enhances glucose excretion in adipose tissue and muscle while preventing glucose synthesis in the liver by inhibiting glycogenolysis and gluconeogenesis.

Insulin resistance in adipose tissue induces increased hydrolysis of triglycerides from adipocytes, resulting in an increase in plasma free fatty acids (FFAs). Insulin resistance in muscle cells lowers glucose absorption, but insulin resistance in liver cells leads to reduced glycogen synthesis, failure to control glucose production, increased lipogenesis, and increased synthesis of proteins such as C-reactive protein (CRP).

When insulin resistance in insulin-sensitive target tissues (muscle, fat, and liver) is present, it results in severe abnormalities such as hyperglycemia, hyperinsulinemia, and hypertriglyceridemia, all of which are major hallmarks of type 2 diabetes (T2D) and metabolic syndrome (MetS).

MetS is a group of metabolic disorders that increase the likelihood of developing cardiovascular disease (CVD). Due to the liver's important participation in insulin resistance and MetS, we are concentrating on hepatic insulin resistance as a primary beginning cause in MetS driving CVD. 



hepatic insulin resistance definition

What is hepatic insulin resistance definition?

  • Insulin resistance is defined as a diminished physiologic response to insulin stimulation of target tissues, most notably the liver, muscle, and adipose tissue. Insulin resistance affects glucose elimination, resulting in a compensatory increase of insulin synthesis from pancreatic beta cells and the resulting hyperinsulinemia.
  • Selective hepatic insulin resistance occurs when insulin fails to properly control hepatic metabolism, resulting in excessive glucose production despite increased rates of lipid synthesis.
  • Metabolic syndrome is a collection of five abnormalities that can result in heart disease, diabetes, stroke, and other health issues. Metabolic syndrome is diagnosed when three or more of the following risk factors are present:
      • High blood glucose (sugar) levels.
      • Low HDL "good cholesterol" levels in the blood.
      • High triglyceride levels in the blood. 
      • Large waist circumference or "apple-shaped" physique.
      • High blood pressure.


Signs and symptoms of hepatic insulin resistance

Signs and symptoms of hepatic insulin resistance

What are hepatic insulin resistance symptoms?

The way you feel does not indicate that you have insulin resistance. You'll need to get a blood test to determine your blood sugar levels.

Similarly, unless you consult a doctor, you won't know if you have most of the other diseases associated with insulin resistance syndrome (high blood pressure, low "good" cholesterol levels, and high triglycerides).

Some indicators of insulin resistance include:

  • A waistline measuring more than 40 inches in men and 35 inches in women.
  • 130/80 or higher blood pressure readings.
  • A fasting glucose level more than 100 mg/dL.
  • A fasting triglyceride level of more than 150 mg/dL.
  • HDL cholesterol level of less than 40 mg/dL in men and less than 50 mg/dL in women.
  • Tags on the skin.
  • Acanthosis nigricans refers to patches of black, velvety skin.



pathophysiology of hepatic insulin resistance

Insulin signaling in insulin-sensitive tissues:

Insulin is an essential endocrine hormone that regulates glucose homeostasis throughout the body. Insulin regulates glucose homeostasis by promoting glucose excretion in muscle and adipose tissues and suppressing glucose synthesis in the liver through inhibition of glycogenolysis and gluconeogenesis. Insulin also affects lipid metabolism by enhancing fatty acid synthesis, lowering lipolysis, and enhancing esterification of free fatty acids.

Insulin's effects on cell metabolism are mediated by a hetero-tetramer receptor found on most cells, particularly liver, adipose, and skeletal muscle cells. The binding of insulin to its receptor triggers a series of events that include receptor auto-phosphorylation on tyrosine residues and tyrosine phosphorylation of binding proteins such as insulin receptor substrates insulin (IRS) 1–6 and other receptors, all of which activate downstream signaling molecules.

IRS proteins appear to play distinct functions in various tissues. IRS-1 appears to be the primary insulin signaling mediator in skeletal muscle, adipose tissue, and pancreatic beta cells. IRS-2 regulates liver metabolism and beta cell proliferation. IRS-3 appears to be involved in fat cell function.


Molecular mechanisms of insulin resistance:

Insulin resistance is a pathophysiological condition in which normal insulin concentrations fail to induce a normal insulin response in target tissues such as adipose, muscle, and liver. To compensate for the hyperglycemia in these people, pancreatic beta cells release extra insulin (hyperinsulinemia). The increased insulin levels have extra impacts on most tissues, particularly those that remain insulin sensitive, such as the kidney and ovary. The failure of pancreatic beta cells to generate enough insulin to overcome deteriorating tissue insulin resistance leads to hyperglycemia and overt T2D over time.

The processes underlying insulin resistance are incompletely understood. Several causes have been hypothesized, including defective insulin synthesis, mutations in the insulin receptor and its substrates, and insulin antagonists, but it appears that post-receptor signaling abnormalities are the primary source of insulin resistance in target tissues.

Early insulin signaling molecules have been found to have lower expression and/or phosphorylation in insulin target tissues of obese and T2D patients.

Increased phosphatase activity, which dephosphorylates intermediary signaling molecules, can disrupt the insulin pathway. While various phosphatases have been identified as insulin inhibitors, in vivo evidence in mice strongly supports protein tyrosine phosphatase 1B (PTP1B) as the primary regulator of insulin signaling.

Obese, insulin-resistant, and T2D individuals have elevated levels of PTP1B expression in their muscle and liver tissues. PTP1B overexpression in the liver resulted in both hepatic and systemic insulin resistance. 


What is the metabolic consequences of hepatic insulin resistance?

hepatic insulin resistance

The liver is an insulin-sensitive organ that regulates energy balance throughout the body. Insulin signaling dysfunction and the development of insulin resistance in the liver can have serious effects for energy balance and metabolism. As a result, hepatic insulin resistance has been proposed as an underlying cause of MetS and its associated abnormalities such as hyperglycemia, dyslipidemia, and elevated inflammatory markers. 


Hepatic insulin resistance and associated hyperglycemia:

Fasting hyperglycemia, which is frequent in people with T2D and MetS, is caused by decreased glucose absorption by peripheral tissues and increased glucose synthesis by hepatocytes that are resistant to insulin action.

When fasting and under insulin-sensitive situations the liver delivers glucose to the brain via glycogenolysis or gluconeogenesis. In contrast, released insulin from pancreatic cells can decrease glucose synthesis in liver cells by inhibiting glycogenolysis and gluconeogenesis in the fed state.

Hepatic insulin resistance is the inability of insulin to decrease glucose synthesis in hepatocytes. Insulin inhibits glucose synthesis by inactivating two major gluconeogenic enzymes, phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6 phosphatase (G6Pase).

Additionally, it appears that glucagon, a counter-regulatory hormone in glucose metabolism, has a role in type 2 diabetes fasting hyperglycemia by promoting hepatic glucose synthesis. Normal people' glucagon levels are generally down-regulated by glucose and dietary consumption, but diabetes patients are unable to lower glucagon adequately in response to glucose or food ingestion.

Animals with a liver-specific inactivation of the insulin receptor have severe hyperglycemia, whereas mice with a deletion of the insulin receptor in skeletal muscle and adipose have normal glucose and insulin levels, implying that hepatic insulin resistance is required to develop hyperglycemia and glucose intolerance. Mice missing IRS-2 in the liver exhibited significant insulin resistance and hyperglycemia as well.

Collectively, data from animal and human research show that insulin resistance in the liver tissue leads to hyperglycemia and the development to MetS and T2D. 


Hepatic insulin resistance and associated dyslipidemia:


Insulin affects hepatic lipid metabolism by promoting mRNA expression of nuclear transcription factors such as sterol regulatory element-binding protein-1c (SREBP-1c), which play an important role in the regulation of de novo lipogenesis (DNL) and triglyceride production. Insulin operates peripherally by promoting the absorption of fatty acids generated by lipoprotein lipase-mediated triglyceride hydrolysis into muscle and adipose tissue.

Insulin resistance has a negative impact on hepatic lipid and lipoprotein metabolism. Hepatic overproduction of very low-density lipoprotein (VLDL) is one of the primary abnormalities. Insulin resistance (in adipose and hepatic tissues) appears to be a major underlying cause of hypertriglyceridemia in people with MetS and T2D, according to evidence from both animal and human research.

Insulin resistance increases hepatic lipid accumulation, which is related to an increase in FFA flow from adipose tissue to the liver. Increased liver absorption of chylomicron remnants and dietary FFAs delivered by chylomicrons results in increased hepatic lipid content. Failure of insulin to regulate hormone-sensitive lipase, the rate-limiting enzyme for adipose tissue triglyceride mobilization, leads to increased lipolysis and FFA flow to other tissues, particularly the liver, in insulin-resistant conditions. Increased circulating FFA levels and FFA flow to the liver, as seen in insulin resistance in T2D patients, are known to cause VLDL overproduction.

Small dense LDL (sdLDL) production and low HDL levels are two main components of metabolic dyslipidemia seen in MetS and T2D patients. In both diabetic and nondiabetic individuals, sdLDL is linked to insulin resistance and hypertriglyceridemia. The activity of two proteins, cholesteryl ester transfer protein (CETP) and hepatic lipase, is responsible for the synthesis of sdLDL in insulin-resistant conditions. CETP facilitates the exchange of VLDL triglyceride for LDL cholesteryl ester, resulting in a triglyceride-rich, cholesterol-free LDL particle. This LDL particle acts as a substrate for hepatic lipase, resulting in triglyceride hydrolysis and the generation of sdLDL. Increased CETP and hepatic lipase activity in insulin resistant and T2D individuals promotes sdLDL production.

Reduced levels of high-density lipoprotein (HDL) "good cholesterol" have also been seen in MetS and T2D patients. Low HDL is related with excessive hepatic VLDL production. Low HDL cholesterol in T2D is caused in part by a reduction in HDL cholesteryl ester and is accompanied by greater HDL triglycerides due to CETP activity. 


Hepatic Insulin resistance and associated pro-inflammatory state:

pro-inflammatory state

MetS is linked to a higher risk of CVD and T2D. Epidemiological studies have demonstrated that classic predisposing factors recognized in the MetS (central obesity, hyperglycemia, hypertension, hypertriglyceridemia, and reduced HDL cholesterol) cannot account for all CVD events found in these patients.

Insulin resistance, obesity, and type 2 diabetes are all linked to a chronic inflammatory state caused by excessive cytokine release, elevated acute phase proteins and other mediators, and activation of an inflammatory signaling network. CRP is a significant human acute phase protein that is primarily generated in hepatocytes in response to inflammatory stimuli.

The CRP and its function in the development of CVD have received a lot of attention in recent years. Prospective studies have found a link between serum CRP levels and MetS components such as abdominal obesity, raised triglycerides, low HDL cholesterol levels, high blood pressure, and fasting glucose levels. CRP has also been demonstrated to be an independent predictor of diabetes and cardiovascular disease.

CRP levels have been observed to correspond with direct measures of insulin resistance and endothelial dysfunction.  There is a large set of data from human, animal, and in vitro research that supports the concept that CRP is a critical component of the syndrome that increases the risk of CVD in people with MetS. CRP has also been proven to play a direct function in atherosclerosis development. 


Is there an association between obesity and hepatic insulin resistance?

obesity and hepatic insulin resistance

Insulin resistance is caused by complex factors such as genetic factors, lifestyle factors, aging, and dietary variables. The most common cause of insulin resistance is visceral adiposity. Visceral obesity has also been identified as a key component of MetS, and increasing visceral fat mass leads to the development of obesity-related illnesses such as insulin resistance, non-alcoholic fatty liver disease (NAFLD), hypertension, diabetes, and CVD.

Chronic systemic inflammation has been implicated in the pathophysiology of obesity-related insulin resistance. There is substantial evidence that adipose tissue not only generates FFA, which leads to insulin resistance in the liver and muscle but also a variety of inflammatory chemicals such as tumor necrosis factor- α (TNF- α) and interleukin-6 (IL-6), which may have local impacts on adipose physiology as well as systemic effects on other tissues.

TNF- α was the first cytokine identified as playing a role in the etiology of insulin resistance due to its ability to block insulin signaling in the liver. TNF- α is overexpressed in obese rats and humans, and its concentration decreases with weight reduction. 


Does hepatic insulin resistance increase the risk of cardiovascular disease?

cardiovascular disease

In many parts of the world, cardiovascular disease, which includes heart disease, stroke, and heart failure, is the leading cause of mortality. CVD is mostly caused by atherosclerosis. Population studies reveal that MetS and its related anomalies are linked to an elevated risk of CVD.

MetS was linked to a greater risk of CVD than dyslipidemia, hypertension, a high homeostasis model assessment of insulin resistance, or obesity considered separately. A meta-analysis verified this, revealing a 2-fold CVD risk for MetS that remained substantial when controlling for established CVD risk variables.

MetS is composed of multiple risk factors for CVD, including hypertension, hyperlipidemia, obesity, procoagulability, and hyperglycemia. Among them, hyperlipidemia, procoagulability, and hyperglycemia are directly caused by hepatic insulin resistance and have a link to CVD.

It has long been recognized that chronic hyperglycemia has a significant impact on the etiology of atherosclerosis. Research using data from 52 nations found that higher-than-optimal blood glucose levels are responsible for 21% of ischemic heart disease (IHD) fatalities and 13% of stroke deaths globally. Furthermore, the UK Prospective Diabetes Study (UKPDS) has shown that rigorous hyperglycemia therapy in type 2 diabetes lowers the risk of complications.

Dyslipidemia is the most prevalent consequence of MetS and type 2 diabetes, according to research. Low HDL-C levels, sdLDL particles, and hypertriglyceridemia are common lipid and lipoprotein abnormalities in insulin resistance. The main cause of dyslipidemia in MetS patients is VLDL overproduction caused by hepatic insulin resistance.

Even in the absence of traditional risk factors such as high LDL cholesterol, hypertension, or smoking, the presence of sdLDL particles significantly elevated the risk of coronary heart disease.

It has also been established that sdLDL is more atherogenic than bigger, more buoyant low-density lipoprotein (LDL) and that intimal proteoglycans have a stronger affinity for sdLDL than large LDL, resulting in more LDL particle penetration into the artery wall.

Hepatic insulin resistance also plays an important role in the inhibition of the fibrinolysis system through the overproduction of Plasminogen activator inhibitor-1 (PAI-1) and fibrinogen. A low level of plasma fibrinolytic activity is strongly associated with an increased risk of coronary artery disease.


What is the treatment of hepatic insulin resistance?

treatment of hepatic insulin resistance

Intensive Lifestyle modifications:

Lifestyle modifications

The cornerstone of insulin resistance therapy is lifestyle modification. Dietary intervention should involve calorie restriction as well as a reduction in high glycemic index foods. Physical exercise boosts calorie expenditure as well as insulin sensitivity in muscle tissue.

Insulin resistance puts people at a significant risk of acquiring T2DM. The Diabetes Prevention Program and its Outcomes Study (DPP & DPPOS) found that lifestyle interventions were both beneficial and cost-effective for diabetes prevention in high-risk people.

  • A nutritional treatment that includes salt reduction, fat reduction, calorie restriction, and food glycemic index considerations.
  • Education, guidance, and customized programs
  • A 7% weight reduction delayed the onset of T2DM by 58 percent.
  • The DPP included a metformin arm that decreased the development of T2DM by 31%. 


Pharmacological Interventions for Blood Glucose Control:

Pharmacological Interventions

While there are no FDA-approved drugs for the treatment of insulin resistance, broad approaches include the following:

  • Metformin: This medicine is licensed for use in polycystic ovarian syndrome and is considered first-line therapy for the treatment of T2DM. The DPP/DPPO trial found that combining metformin with lifestyle modifications was both medically beneficial and cost-effective. Despite concerns about usage in mild to moderate renal insufficiency, some organizations, including the American Geriatric Society and the KDIGO (Kidney Disease Improving Global Outcomes) recommendations, support use if the glomerular filtration rate (GFR) is more than 30.
  • Glucagon-like peptide one inhibitors: GLP-1 receptor agonists activate the pancreatic GLP-1 receptors, boosting insulin release while blocking glucagon secretion. GLP-1 agonist use is linked to weight loss, which may improve Insulin Resistance. Liraglutide is an anti-obesity medication that has been authorized by the FDA.
  • Sodium-glucose cotransporter two inhibitors: SGLT2 inhibitors improve urine glucose excretion, lowering plasma glucose levels and exogenous insulin needs. The use of SGLT2 inhibitors has also been linked to weight reduction, which may help to improve insulin resistance.
  • Thiazolidinediones: TZDs increase insulin sensitivity by enhancing insulin-dependent glucose clearance in muscle and adipose tissue while lowering hepatic glucose production. Although effective, secondary weight gain and fluid retention, as well as related cardiovascular risks, restrict their usage.
  • Dipeptidyl peptidase-4 inhibitors: DPP-4 inhibitors work by inhibiting the breakdown of endogenous GLP-1 and gastric inhibitory polypeptide (GIP) thus prolonging their activity.

Individuals receiving insulin therapy:

  • When substantial dosages of insulin (more than 200 units per day) are necessary to increase tolerance and absorption, concentrated insulin formulations are preferred. U-500 and U-200 Lispro, and U-300 Glargine are now available.


Surgical options:

bariatric surgery

For suitable individuals suffering from obesity, surgical intervention in the form of a gastric sleeve, banding, or bypass is offered. Excess fat reduction from bariatric surgery enhances insulin sensitivity. The STAMPEDE study found strong evidence that bariatric surgery can help people with type 2 diabetes.



Insulin resistance

Insulin resistance is a pathophysiological condition in which normal insulin concentrations fail to induce a normal insulin response in target tissues such as adipose, muscle, and liver 

The liver is an insulin-sensitive organ that controls the body's energy balance. Insulin signaling failure and insulin resistance development in the liver can have major consequences for energy balance and metabolism. As a result, hepatic insulin resistance has been hypothesized as a possible cause of MetS and its accompanying abnormalities, such as hyperglycemia, dyslipidemia, and increased inflammatory markers.

Chronic inflammation linked with visceral obesity is now well known to cause insulin resistance in the liver. The generation of abnormal cytokines characterizes chronic inflammation. These cytokines inhibit insulin signaling in hepatocytes 

Hepatic insulin resistance, in turn, leads to reduced suppression of glucose synthesis by insulin in hepatocytes, resulting in hyperglycemia.

Insulin resistance in the liver tissue leads to hyperglycemia and the development of MetS and T2D. In insulin-resistant states Increased circulating FFA levels and FFA flow to the liver are known to promote VLDL overproduction in T2D patients with insulin resistance.

There is a relationship between serum CRP levels and MetS components such as abdominal obesity, elevated triglycerides, poor HDL cholesterol levels, high blood pressure, and fasting glucose levels. CRP has also been shown to be a reliable predictor of diabetes and cardiovascular disease.

The pathogenesis of obesity-related insulin resistance has been linked to chronic systemic inflammation. There is substantial evidence that adipose tissue produces not only FFA, which causes insulin resistance in the liver and muscle but also a variety of inflammatory chemicals such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), which may have local effects on adipose physiology as well as systemic effects on other tissues.

MetS is characterized by a number of CVD risk factors, including hypertension, hyperlipidemia, obesity, procoagulability, and hyperglycemia. Hyperlipidemia, procoagulability, and hyperglycemia are all directly determined by hepatic insulin resistance and have been linked to CVD.

Management of hepatic insulin resistance relies heavily on lifestyle modifications that aim to reduce risk factors of metabolic syndrome and CVD.

Dietary modifications include: salt reduction, fat reduction, calorie restriction, and low-glycemic index food consumption. Weight loss significantly decreases the risk of T2Dand MetS

There are no FDA-approved drugs for the treatment of hepatic insulin resistance. But the following drugs can be tried under a doctor’s supervision: metformin, GLP-1 receptor agonists, SGLT2 inhibitors, TZDs, and DPP-4 inhibitors.

Surgical options in selected cases: gastric sleeve, banding, or bypass.