Insulin physiologic effects

A challenge posed to researchers was therefore to account for diverse physiological effects emanating from the same receptor/hormone interaction. Structurally, the insulin receptor (IR) is a tetrameric protein, composed of two smaller extracellular a units and two larger transmembrane [3 units (see Figure 4.20a). 

In humans the possibility of mimicking caloric restriction by addition of supplements, fiber, micronutrients, and others that form the group of geronto-ceuticals (i.e., potential antiaging cocktails that may mimic the metabolic or physiological effects of CR) bodes well for the possibility that the extended life and health spans associated with lower body temperature and insulin levels may ultimately be attainable without reduced food consumption or appetite.10... 

Glucose-dependent insulinotropic polypeptide is originally known as gastric inhibitory polypeptide (GIP), which is a 42-residue peptide first isolated by Brown and Dryburgh (14). It is secreted from the duodenum and proximal jejunum in response to food. Two major physiological effects of GIP are inhibition of gastric acid secretion and stimulation of insulin release. 

Dimitriadis GD, Raptis SA, Newsholme EA. Integration of some biochemical and physiologic effects of insulin that may play a role in the control of blood glucose concentration. In LeRoith D, Taylor SI,... 

Glucagon-like peptide-1 (GLP-1) is an incretin, a natural peptide hormone secreted in response to food intake. Incretins have multiple physiological effects to lower blood sugar, including the stimulation of insulin release and the inhibition of glucagon release following meals (28). 

A combined treatment with neuraminidase and P galactosidase abolishes binding of insulin with, of course, elimination of all its physiological effects. Treatment with neuraminidase alone does not prevent the binding, but interferes with the cell s response to insulin as if the presence of sialic acid were indispensable to communicate the message imparted from the formation of the insulin receptor complex to the various cell constituents responsible for the insulin response. 

Fig. 7.2 The incretin system. Relationship between the physiological effects of GLP-l and GIP on insulin secretion and the action of targets implied in T2DM treatment. GLP-l and GIP are released from enteroendocrine cells after nutrient ingestion to stimulate insulin secretion. However, their activity is reduced because of the cleavage of DPP-IV at the second residue of GLP-l and GIP. Two alternatives to avoid the cleavage are administration of incretin mimetics ot DPP-IV inhibitors...

It is apparent that this stepwise approach may finally permit precise analysis, in fundamental terms, of the manner by which a hormone acts to produce its physiological effects. It will have been recognized that the strategic proposals presented do not represent a new approach to the problem of hormone action. Essentially they derive from the approach taken by students of insulin action. From Gemmill s observation (1940) that insulin acts on diaphragm muscle in to promote glycogen synthe-... 

Table II represents the author s estimate of the physiological significance of the in vitro findings with hormones reported in the literature, as based upon the above criteria. It will be seen that a sizable number of hormones exert in vitro effects which are comparable in their essentials to the physiological effects observed in vivo. Among these are seen all chemical classes of hormones with the exception of the steroids protein— insulin polypeptides—ACTH, antidiuretic hormone (ADH), oxytocin, and glucagon or hyperglycemic factor (HGF) and amino acid derivatives —epinephrine and nor-epinephrine. The remaining hormones listed, in which physiologically meaningful in vitro results have not been as yet achieved, may be subdivided into two groups one, wherein little work has been attempted (as with parathormone, prolactin, etc.) the other, wherein extensive in vitro studies have been carried out.

No attempt has been made to review the fragmentary and scattered data which bear on the general problem of the mechanisms of hormone action. Instead this essay has attempted to define the general problem of hormone action in terms of separate questions which may be approached experimentally, and to this end specific strategic proposals have been advanced. These proposals are not unique. Using this experimental outline as a basis for discussion, we have attempted to evaluate some of the available evidence which bears on the action of three diverse mammalian hormones of which our knowledge seems most advanced —insulin, epinephrine, and ACTH. All of these hormones act in vitro to reproduce, in their essentials, a characteristic physiological effect. In each case, the in vitro response to the hormone appears clearly to be the end product of a... 

The therapeutic use of homologous human proteins - including insulin, growth hormone, and colony stimulating factors - in replacement therapy, has been adequately supported by subchronic toxicity studies in animal species reactive to their pharmacological or physiological effects. Extension to chronic studies has usually not provided valuable additional safety information. 

Most of the polypeptide hormones and catecholamines seem to exert most, if not all, of their physiological effects by increasing the activity of adenylate cyclase, with a subsequent increase in intracellular cAMP concentration in target tissues (Table 6) (Robison et al., 1971). The two most notable exceptions to this are growth hormone and insulin, although there is still some debate regarding the effect of insulin on adenylate cyclase activity. 

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