Effects of Insulin

Brewers and bakers dried yeasts are used as dietary supplements. They contribute some protein and trace minerals, and some B vitamins, but no vitamin C, vitamin B 2 or fat-soluble vitamins. The glucose tolerance factor (GTE) of yeast, chromium nicotinate, mediates the effect of insulin. It seems to be important for older persons who caimot synthesize GTE from inorganic dietary chromium. The ceU wall fraction of bakers yeast reduces cholesterol levels in rats fed a hypercholesteremic diet. 

FIGURE 23.22 The metabolic effects of insulin. As described in Chapter 34, binding of insulin to membrane receptors stimulates the protein kinase activity of the receptor. Subsequent phosphorylation of target proteins modulates the effects indicated. 

There is weak expression of PPARy in muscle, liver and other tissues, enabling TZDs to support the effects of insulin in these tissues, notably increased glucose uptake in muscle and reduced glucose production in liver. TZDs may also affect nutrient metabolism by skeletal muscle through a direct mitochondrial action that is independent of PPARy. 

Thiazolidinediones (PPARy-agonists) Thiazolidine-diones ( pioglitazone, rosiglitazone) lower blood glucose levels in animal models of insulin resistance and also in insulin resistant patients. They are agonists of the peroxisome proliferator-activated receptor y (PPARy). Because they enhance the effect of insulin and reduce serum insulin levels in insulin resistant patients, thiazolidinediones are usually referred to as insulin sensitizers . 

The insulin receptor is a transmembrane receptor tyrosine kinase located in the plasma membrane of insulin-sensitive cells (e.g., adipocytes, myocytes, hepatocytes). It mediates the effect of insulin on specific cellular responses (e.g., glucose transport, glycogen synthesis, lipid synthesis, protein synthesis). 

Insulin Receptor. Table 1 The effect of insulin on energy and glucose homeostasis... 

Other, more general effects of insulin on cellular function include stimulation of cell growth (increase in DNA and protein synthesis), inhibition of apoptosis, and modulation of ion-channel activity. 

Also, phosphorylation of Akt results in activation of sterol regulatory-element binding protein 1 (SREBP1), a key transcription factor involved in regulation of lipogenic enzymes. In addition, some of the effects of insulin on cell proliferation and survival may be explained by an Akt-dependent inhibition of apoptosis through phosphorylation and inactivation of proa-poptotic proteins (e.g., BAD, Caspase 9). 

Insulin resistance occurs when the normal response to a given amount of insulin is reduced. Resistance of liver to the effects of insulin results in inadequate suppression of hepatic glucose production insulin resistance of skeletal muscle reduces the amount of glucose taken out of the circulation into skeletal muscle for storage and insulin resistance of adipose tissue results in impaired suppression of lipolysis and increased levels of free fatty acids. Therefore, insulin resistance is associated with a cluster of metabolic abnormalities including elevated blood glucose levels, abnormal blood lipid profile (dyslipidemia), hypertension, and increased expression of inflammatory markers (inflammation). Insulin resistance and this cluster of metabolic abnormalities is strongly associated with obesity, predominantly abdominal (visceral) obesity, and physical inactivity and increased risk for type 2 diabetes, cardiovascular and renal disease, as well as some forms of cancer. In addition to obesity, other situations in which insulin resistance occurs includes... 

Propranolol may alter the effectiveness of insulin or oral hypoglycemic dm. Dosage adjustments may be necessary. 

When certain drug s are administered with insulin, a resultant decrease or increase in hypoglycemic effect can occur. Display 49-1 identifies selected dragp that decrease the hypoglycemic effect of insulin. 

DISPLAY 49-1 Select Drugs That Decrease the Hypoglycemic Effect of Insulin... 

FIGURE 12 Effect of insulin released from microspheres of PCPP-SA 50 50 injected subcutaneously in streptozotocin-diabetic rats. Details were as described in the text. 

Insulin sensitizer A substance that increases the action of insulin in peripheral tissues by reducing the effects of insulin resistance. 

When the actions of one hormone oppose the effects of another, the result is antagonism. For example, insulin decreases blood glucose and promotes the formation of fat. Glucagon, on the other hand, increases blood glucose and promotes the degradation of fat. Therefore, the effects of insulin and glucagon are antagonistic. 

Table 11.1 Some metabolic effects of insulin. These effects are generally countered by other hormones (glucagon and, in some cases, adrenaline). Hence, the overall effect noted often reflects the relative rates of these hormones present in the plasma...

Metabolic pathway Target tissue Effect of insulin Effect of glucagon... 

Hypoglycemia and weight gain are the most common adverse effects of insulin. Treatment of hypoglycemia is as follows ... 

Al. Abraham, S., Cady, P., and Chaikoff, I. L., Effect of insulin in vitro on pathways of glucose utilization other than Embden-Meyerhof in rat mammary gland, y. Biol. Chem. 224, 955-962 (1957). 

It was discovered nearly 20 years ago that V(V) as vanadate and V(IV) as vanadyl can mimic some of the effects of insulin (stimulate glucose uptake and oxidation and glycogen synthesis) (512, 513). Vanadate is an effective insulin mimetic in the diabetic rat (514), but has proved to be too toxic for human use. Vanadyl, as VOS04, is also unsuitable because high doses are needed on account of its poor oral absorption. Vanadium complexes with organic ligands have proved to be less toxic and can have improved aqueous solubility and lipophil-icity. 

While our data using this technique are still preliminary, we have observed that 25 yU/ml insulin inhibits the rate of calcium efflux from renal slices (28). This effect of insulin was gradually reduced at the higher concentrations of insulin. The effects of insulin on calcium exchange appear to be localized in the mitochondrial compartment. Further work is needed to determine whether insulin affects specific enzyme systems which are known to play a role in renal calcium transport, and which cellular or subcellular compartments are involved. This would substantially increase our understanding of the regulation of urinary calcium excretion, and of ways in which excessive loss of calcium by this route might be avoided. 

In adipose tissue, insulin stimulation suppresses triglyceride hydrolysis (to free fatty acids and glycerol) by activating cAMP phosphodiesterase (cAMP PDE). Cyclic AMP, (3, 5 cAMP), is required to stimulate hormone sensitive lipase (HSL), the enzyme which hydrolyses triglyceride within adipocytes PDE converts active 3, 5 cAMP to inactive 5 AMP thus preventing the stimulation of HSL. The net effect of insulin on lipid metabolism is to promote storage. 

Growth promoting effects of insulin occur via interaction of the IR with Grb-2 or SHC adaptor proteins. The cascade from Grb-2 or SHC includes ras, raf, sos and MEK, culminating in activation of the gene transcription factor MAPK. Refer again to Figure 4.21. 

P.I. Karl, K.L. Alpy, and S.E. Fisher. Amino acid transport by the cultured human placental trophoblast Effect of insulin on AIB transport. Am J Physiol. 262 C834—C839 (1992). 

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