Origins: TBL 6 Flashcards
insulin is a signal of the “fed state” and promotes storage of carbohydrates and fats (the primary energy substrates)
The insulin signaling pathways mediate metabolic and growth-promoting functions, such as translocation of vesicles containing GLUT4 glucose transporters to the plasma membrane, stimulation of glycogen and protein synthesis, and initiation of specific gene transcription.
Ghrelin is secreted by the empty stomach stimulating orexigenic neurons to produce neuropeptide Y (NPY), which increases appetite.
- Leptin is released when fat storage (in adipose tissue) is sufficient, and signals the brain to “stop eating”.
- When leptin levels increase, NPY levels fall.
Leptin also acts in other tissues, such as liver and muscle, where it activates AMP- dependent kinase.
Remember that AMPK promotes energy producing pathways (fat mobilization and oxidation) and down-regulates fatty acid synthesis (energy storage).
Dysfunction in leptin levels and activity is associated with obesity.
- Adiponectin and resistin are adipose-derived peptide hormones that are associated with insulin resistance.
- Adiponectin sensitizes organs to the effects of insulin, whereas resistin is so-named for its ability to block the action of insulin in adipocytes.
Through AMPK activation, adiponectin stimulates appetite and reduces energy expenditure. In muscle, it increases fatty acid uptake from blood and the rate of fat utilization. In liver, it blocks fatty acid synthesis and gluconeogenesis. And it stimulates glucose uptake and catabolism in both liver and muscle.
Resistin, which has the ability to block the action of insulin in adipocytes, seems to be higher in abdominal fat than in subcutaneous fat. This is consistent with the correlation between abdominal fat and the risk of developing type 2 diabetes.
As individuals become obese, Adiponectin levels fall, and with it, reduced fatty acid oxidation occurs in tissues.
Weight reduction results in a decrease in the size of fat cells rather than a
decrease in number. After weight loss, the amount of LPL, an enzyme involved in the transfer of fatty acids
from blood triacylglycerols to the triacylglycerol stores of adipocytes, increases.
These signals are integrated and relayed through the
hypothalamus. Destruction of specific regions of the hypothalamus can lead to overeating and obesity or to
anorexia and weight loss.
Increased circulating levels of nonesterified (or free) fatty acids (NEFA) are observed in obesity and are
associated with insulin resistance.
For a diagnosis of metabolic
syndrome, at least three of the following components should be evident:
Increased waist circumference: 40 inches or more for men, 35 inches or more for woman
Elevated triglycerides (≥150 mg/dL)
Reduced HDL (<40 mg/dL for men, <50 mg/dL for women)
Elevated blood pressure (≥130/85 mm Hg)
Elevated fasting glucose (≥100 mg/dL)
A characteristic of the metabolic syndrome is insulin resistance. Part of this resistance is caused by
altered insulin release from the β-cells of the pancreas under hyperlipidemic conditions.
Salicilates. Treatment of diabetic patients with salicilates lowers blood glucose concentrations and prevents fat-induced muscle insulin resistance.
Biguanides, such as metformin (Glucophage), activate AMPK and can mimick the effects of adiponectin.
The thiazolidinedione (TZDs) class of antidiabetic drugs (such as rosiglitazone) are insulin-sensitizing drugs that are agonists of the transcription factor PPAR-g (peroxisome-proliferator activated receptor gamma).
PPAR-g also stimulates adipocyte differentiation and modulates lipid metabolism in adipocytes, which increases the capacity for lipid storage. It also increases the concentration of adiponectin in plasma. All of these effects likely influence the profile of circulating lipids, and indirectly influence (stimulate) the ability of muscle and liver to process glucose.
that increasing the supply and oxidation of fatty acids leads to cellular accumulation of acetyl-CoA, NADH and ATP, which allosterically inhibit pyruvate dehydrogenase (PDH)
these studies pointed to glucose uptake rather than glucose phosphorylation as the rate-limiting barrier for muscle glucose disposal in type 2 diabetic subjects (Shulman, 2000).
What does happen to muscle mitochondria during the initial phases of overnutrition and insulin resistance? the carbon load on the muscle’s oxidative machinery begins to mount, such that the rate of fatty acid catabolism persistently surpasses the drive for ATP resynthesis.
nutrient-induced substrate switching is often compromised in the settings of obesity and type 2 diabetes, commonly known as “metabolic inflexibility”
