Golgi Apparatus A Level

[Liese Hittson]

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The level of diacylglycerol (DAG) in the Golgi apparatus is crucial for protein transport to the plasma membrane. Studies in budding yeast indicate that Sec14p, a phosphatidylinositol (PI)-transfer protein, is involved in regulating DAG homeostasis in the Golgi complex. Here, we show that Nir2, a peripheral Golgi protein containing a PI-transfer domain, is essential for maintaining the structural and functional integrity of the Golgi apparatus in mammalian cells. Depletion of Nir2 by RNAi leads to substantial inhibition of protein transport from the trans-Golgi network to the plasma membrane, and causes a reduction in the DAG level in the Golgi apparatus. Remarkably, inactivation of cytidine [corrected] 5'-diphosphate (CDP)-choline pathway for phosphatidylcholine biosynthesis restores both effects. These results indicate that Nir2 is involved in maintaining a critical DAG pool in the Golgi apparatus by regulating its consumption via the CDP-choline pathway, demonstrating the interface between secretion from the Golgi and lipid homeostasis.

Insulin is initially synthesized in the endoplasmic reticulum and Golgi apparatus as proinsulin; it is then cleaved to insulin and C-peptide. Although insulin and C-peptide are co-secreted in equal molar proportions, the ratio of serum insulin to C-peptide is 1:5-15. Fifty to sixty percent of insulin is extracted by the liver before it reaches the systemic circulation, and it has a half-life of only 4 minutes. In contrast, C-peptide and proinsulin are excreted via the kidney. [2]

Insulin is an anabolic hormone that promotes glucose uptake, glycogenesis, lipogenesis, and protein synthesis in skeletal muscle and fat tissue through the tyrosine kinase receptor pathway. Through these functions, insulin serves as the most important factor in maintaining plasma glucose homeostasis, counteracting glucagon and other catabolic hormones such as epinephrine, glucocorticoid, and growth hormone. In addition, the literature suggests that insulin plays a pivotal role in maintaining normal neurologic function, bone development, and hair growth and in preventing aging. [3, 4]

When plasma glucose levels are elevated, glucose diffuses to beta cells through glucose transporter 2 (GLUT2) and activates the glycolysis pathway, leading to elevated adenosine triphosphate (ATP) levels. Increasing ATP levels induce ATP-sensitive K+ channels to shut down, subsequently stimulating depolarization of the beta-cell membrane. [5] Then, voltage-gated Ca2+ channels are opened to increase cytosolic Ca2+ and trigger insulin exocytosis. [2] However, high insulin levels in the hypoglycemic state have been found; an example is insulinoma, in which insulin is secreted at a high rate independent of the plasma glucose level.

Interestingly, oral administration of glucose is more effective at increasing insulin secretion than is intravenous glucose administration; this is called the "incretin effect." Carbohydrate meals potentiate insulin secretion through multiple gastrointestinal hormones (incretin hormones), including cholecystokinin, glucagonlike peptide-1 (GLP-1), and gastric-inhibiting polypeptide (GIP). [2, 6]

A standard insulin test measures endogenous and exogenous insulin. In patients not receiving exogenous insulin, serum insulin levels reflect the quantitative functioning of pancreatic beta cells. Calculations based on plasma insulin and glucose concentrations can be used to determine insulin sensitivity and resistance. Measurement of insulin levels is also helpful in differentiating between type 1 and type 2 diabetes and can assist in identifying causes of hypoglycemia.

Normal insulin levels vary widely and depend on age, gender, and race. In addition, insulin tests demonstrate a minimal cross-reaction with proinsulin and insulin-like growth factors 1 and 2, with the degree of variability depending on the brand of the testing toolkit and technique used.

The pattern of insulin secretion in response to a glucose load depends on the route of glucose administration and, in cases of oral administration, the meal composition. [7] The numbers mentioned in table 1 (below) provide a broad estimate of normal values in adults; however, standardized reference values are yet to be determined due to the significant variability among immunoassays used today. [8]

A study by Gabay et al indicated that insulin resistance in female adolescents with obesity may have a negative impact on brain structure and function. The report found, for example, that in the study population, the insular cortices in such patients tended to be thinner, a phenomenon that was not seen in male adolescents with obesity and insulin resistance. [12]

Insulin testing is used to assist in identifying causes of hypoglycemia (plasma glucose levels < 55 mg/dL). When spontaneous hypoglycemia does not recur, a 72-hour fasting test is performed to provoke hypoglycemia. [13] Insulin levels in different conditions are described below:

Insulin levels can be used to assess insulin resistance versus sensitivity. In insulin resistance, the ability of cells to respond to the action of insulin in transporting glucose into tissues is diminished; consequently, the resistant individual begins secreting above-normal amounts of insulin to obtain a quantitatively normal response.

Insulin resistance develops long before the appearance of disease signs. A study by Kraft found borderline diabetes in 14% of subjects with normal oral glucose tolerance tests who had been randomly referred for such evaluation. [15]

Each of these methods has its own limitations. The lack of standardization of the insulin assay procedures prevents the comparison of results between studies; consequently, studies can be compared only qualitatively. The American Diabetes Association (ADA) organized a task force to standardize insulin assays. [16]

HOMA equations have been one of the tools widely used in research to estimate insulin resistance. The two equations (which use fasting blood levels) are as follows, with HOMA-IR used to assess insulin resistance and HOMA-B used to assess pancreatic beta cell function [17, 18] :

Fasting insulin levels can serve as a tool to help guide the choice of therapy in patients newly diagnosed with type 2 diabetes. A study by Saxena et al found that such patients with normal to low initial fasting serum insulin levels responded better to glipizide than to metformin. On the other hand, those with high fasting serum insulin levels responded significantly better to metformin than to glipizide. [19]

Using the HOMA index, a pediatric study by Genovesi et al indicated that, just as a relationship between degree of insulin resistance and risk of hypertension exists in children with excess weight, the same holds true in youngsters of normal weight. The investigators noted that while children with higher body mass index (BMI) z-scores had greater HOMA index values, the HOMA index was linked to the systolic blood pressure z-score regardless of weight class. [20]

Catherine Anastasopoulou, MD, PhD, FACE Associate Professor of Medicine, The Steven, Daniel and Douglas Altman Chair of Endocrinology, Sidney Kimmel Medical College of Thomas Jefferson University; Einstein Endocrine Associates, Einstein Medical Center

Catherine Anastasopoulou, MD, PhD, FACE is a member of the following medical societies: American Association of Clinical Endocrinology, American Society for Bone and Mineral Research, Endocrine Society, Philadelphia Endocrine Society

Disclosure: Nothing to disclose.

Parichart Junpaparp, MD Resident Physician, Department of Internal Medicine, Albert Einstein Medical Center

Parichart Junpaparp, MD is a member of the following medical societies: American College of Physicians, Medical Council of Thailand

Disclosure: Nothing to disclose.

Saranya Buppajarntham, MD Resident Physician, Department of Internal Medicine, Albert Einstein Medical Center

Saranya Buppajarntham, MD is a member of the following medical societies: American College of Physicians

Disclosure: Nothing to disclose.

1Department of Internal Medicine, Section of Gastroenterology, University of Nebraska Medical Center, Omaha, Nebraska
2Research Service, U.S. Department of Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, Nebraska
3Department of Internal Medicine, Section of Diabetes, Endocrinology, and Metabolism, University of Nebraska Medical Center, Omaha, Nebraska
4Department of Internal Medicine, Section of Cardiovascular Medicine, University of Nebraska Medical Center, Omaha, Nebraska
5Fred & Pamela Buffet Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska

After drinking stops, damaged organs may regain partial function or even heal completely, depending on the extent of organ damage and whether there is relapse (i.e., resumption of drinking). Organ damage due to heavy drinking is greatest in the liver, in part because the liver has higher levels of enzymes that catalyze the metabolism of acetaldehyde from alcohol. Acetaldehyde is more toxic than ethanol because it is highly reactive and binds to biomolecules (e.g., proteins, lipids, nucleic acids) and disrupts their function.3,5 However, even after years of chronic alcohol use, the liver has remarkable regenerative capacity and, after sustained cessation of drinking, can recover a significant amount of its original mass.6

With continued excessive drinking, about 20% to 40% of heavy-alcohol consumers with steatosis develop alcoholic steatohepatitis (ASH), characterized by fatty liver, inflammation with accumulation of neutrophils, ballooning degeneration of hepatocytes with or without Mallory-Denk bodies, and pericentral and perisinusoidal fibrosis. The severity of ASH can range from mild to severe and is superimposed on chronic liver disease. Severity of ASH can be assessed by the model for end-stage liver disease (MELD). A MELD score greater than 20 has been proposed as defining severe ASH with approximately 20% mortality.1 Steatohepatitis symptoms include reduced appetite, nausea and vomiting, abdominal pain, fatigue, and weakness. People with severe alcoholic hepatitis exhibit jaundice (yellowing of the skin), dark urine, kidney failure, and confusion. ASH is diagnosed by a serum AST:ALT ratio greater than 1.5:1 with absolute ALT and AST numbers not exceeding 400 international units per liter, increased GGT, serum bilirubin greater than 3 mg/dl, and documented heavy alcohol use until 8 weeks prior to seeking help.15 Ultrasound and magnetic resonance analyses are additionally used to confirm ASH. Currently, hepatologists recommend liver biopsies for diagnosis of ASH, as one-third of patients who are asymptomatic can show advanced fibrosis histologically.10 As for steatosis, the major therapy recommended for mild ASH and severe ASH with systemic inflammatory response syndrome is abstinence from alcohol consumption. This provides the best long-term outcome for survival and recovery. Indeed, Kirpich et al. (2017) reported that after 2 weeks of abstinence, patients who presented with inflammation and increased serum endotoxin showed improvement, as indicated by decreased serum AST, ALT, and cytokeratin 18 (a sensitive marker of liver injury), as well as lower levels of tumor necrosis factor alpha and endotoxin.16 In other articles in this topic series, information is given on pharmacological therapy, in addition to cognitive behavioral therapy, which is known to be key to preventing relapses during abstinence; both of these therapies show increased recovery from ALD.6 In addition, nutritional supplementation is beneficial for recovery from ALD.10

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