Hyperinsulinemic

Insulin and Amylin. Insulin is a member of a family of related peptides, the insulin-like growth factors (IGFs), including IGF-I and IGF-II (60) and amylin (75), a 37-amino acid peptide that mimics the secretory pattern of insulin. Amylin is deficient ia type 1 diabetes meUitus but is elevated ia hyperinsulinemic states such as insulin resistance, mild glucose iatolerance, and hypertension (33). Insulin is synthesized ia pancreatic P cells from proinsulin, giving rise to the two peptide chains, 4. and B, of the insulin molecule. IGF-I and IGF-II have stmctures that are homologous to that of proinsulin (see INSULIN AND OTHER ANTIDIABETIC DRUGS). 

Metabolic diseases In the pancreatic (3-cells, KATP channel derived from >SUR1 and Kir6.2, links cellular metabolism to electrical activity and regulates insulin secretion. Mutations in SUR1 and Kir6.2 that result in loss of Katp channel function have been identified in families with familial persistent hyperinsulinemic hypoglycemia of infancy (PHHI). 

Persistant hyperinsulinemic hypoglycemia of infancy (PHHI) SUR1 subunits of ATP-sensitive potassium channels (KATP) Sulfonylurea... 

Data in part from Ackerman NJ, Clapham DE Ion channels— basic science and clinical disease. N Engl J Med 1997,-336 1575. Other channelopathies include the long QT syndrome (MIM 192500) pseudoaldosteronism (Liddle syndrome, MIM 177200) persistent hyperinsulinemic hypoglycemia of infancy (MIM 601820) hereditary X-linked recessive type II nephrolithiasis of infancy (Dent syndrome, MIM 300009) and generalized myotonia, recessive (Becker disease, MIM 255700). The term "myotonia" signifies any condition in which muscles do not relax after contraction. 

A brief overview about the fundamental principles of the pathogenesis of skeletal muscle insulin resistance and its contribution to the development of type 2 diabetes mellitus is given in the following. Priority is given to the role of lipid metabolism, which is the main field of the reported spectroscopic studies. Furthermore, the technique of euglycemic hyperinsulinemic glucose clamp is described allowing determination of the individual insulin sensitivity of musculature. The role of IMCL in insulin resistance of the skeletal muscle is discussed. 

Increase of IMCL content was also clearly less pronounced under lipid infusion without hyperinsulinemic conditions (protocol [3]). This protocol was carried out in a very similar way by Krssak et who reported that elevation of FFA without hyperinsulinemia does not alter IMCL content. In contrast to those findings are the results of Boden et al. who observed a massive increase of IMCL under similar conditions as in protocol [3], but only a low increase after protocol [1]. The reasons for these discrepancies are still debated. 

Before and after the dietary interventions, IMCL was measured in TA and SOL, and insulin sensitivity was assessed by a euglycemic hyperinsulinemic glucose clamp. 

Hypoglycaemic and hyperinsulinemic effects of some Egyptian herbs used for the treatment of diabetes mellitus (type II) in rats. Egypt J Pharm Sci 1995 36(1-6) 331-342. 

Glucagon, used to treat persistent hyperinsulinemic hypoglycemia of infancy, caused erythema necrolyticum migrans in two neonates (17). 

There has been one previous report of acanthosis nigricans in a woman who received human pituitary extract (62). This condition is usually seen in hyperinsulinemic states, including diabetes mellitus and acromegaly over-stimulation at the IGF-I receptor is probably the final common pathway. 

Brichard, S.M., A.M. Pottier, and J.C. Henquin. 1989. Long term improvement of glucose homeostasis by vanadate in obese hyperinsulinemic fa/fa rats. Endocrinology 125 2510-16. 

Non-insulin-dependent diabetes mellitus Persistent hyperinsulinemic hypoglycemia of infancy... 

Thomas PM, Cote GJ, Wohllk N, Haddad B, Mathew PM, Rabl W, Aguilar-Bryan L, Gagel RF, Bryan J. Mutations in the sulfonylurea receptor gene in familial persistent hyperinsulinemic hypoglycemia of infancy. Science 1995 268(5209) 426-429. 

Thomas PM, Wohllk N, Huang E, Kuhnle U, Rabl W, Gagel RF, Cote GJ. Inactivation of the first nucleotide-binding fold of the sulfonylurea receptor, and familial persistent hyperinsulinemic hypoglycemia of infancy. Am J Hum Genet 1996 59(3) 510-518. 

When studied under more controlled conditions using the eug-lycemic hyperinsulinemic clamp method, it is apparent that chronic treatment of insulin-resistant rats with PPARy agonists can substantially improve peripheral insulin-stimulated glucose disposal and the ability of insulin to suppress hepatic glucose production (67, 71, 72). 

Euglycemic Hyperinsulinemic Glucose Clamp Technique in Anesthetized Rats... 

The effects of counterregulatory hormones on insulin-induced glucose utilization by individual tissues in rats, using the euglycemic hyperinsulinemic clamp technique combined with an injection of 2-[l-3H]-deoxyglucose, were studied by Marfaing et al. (1991). 

Lee et al. (1994) studied the metabolic effects of troglitazone on fructose-induced insulin resistance with the euglycemic hyperinsulinemic clamp technique in rats. 

Hulman et al. (1993) studied insulin resistance in the conscious spontaneously hypertensive rat with the euglycemic hyperinsulinemic clamp technique. 

For the assessment of the side effect potential of the candidate compound on peripheral insulin sensitivity, multiple oGTTs can be performed during the treatment period or the animal study is finished by a hyperinsulinemic-euglycemic glucose clamp study. 

Apweiler et al. (1995) administered BM 13.09143 to lean and obese Zucker rats and performed hyperinsulinemic-euglycemic clamp studies in these animals. 

CRITICAL ASSESSEMENT OF THE METHOD The results of metabolic tissue parameters in liver, and muscle must be interpreted carefully, when a hyperinsulinemic-euglycemic glucose clamp study is performed at the end of the treatment period. Under clamp conditions these tissue parameters are mainly influenced by the hyperinsulinemic condition during the clamp study than by the compound s effect itself. 

---