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figure 7-12 Primary amino acid sequence of human somatostatin and its relationship to preprosomatostatin. Native somatostatin has a disulfide bond connecting amino acids 3 and 14.

peptide that is structurally homologous to a neuropeptide known as calcitonin gene-related peptide (CGRP) (CGRP is discussed in Figure 9-4).

Amyloid is a highly insoluble protein that is deposited in the pancreas of elderly type I diabetics; it is readily visualized at the light microscopic level. It is not known by what mechanism amyloid accumulation occurs in diabetics. Although amyloid-like material has been known to be associated with the pancreas since 1901, amyloid was not solubilized until 1986. Knowledge of the amino acid sequence of IAPP has permitted, through recombinant techniques, the characterization of both the cDNA and a prepro-IAPP, as well as the gene.

Pro-IAPP is packaged along with proinsulin into the secretory granules of the /3-cell; and then mature forms of both peptides are cosecreted. The biological function of IAPP is believed to be related to its ability to antagonize insulin's stimulation of glucose uptake by muscle cells.

F. Leptin

The maintenance of body weight is a complex process involving homeostasis of nutrient intake (carbohydrate, protein, and fat) as well as the metabolic processes of gluconeogenesis and glycolysis in muscle and liver cells and particularly in adipose cells. Normally higher vertebrates maintain the body's energy reserve of fat (triglycerides) with high precision; thus, a typical nonobese, healthy adult would have a body mass containing 15-20% fat. However, in some vertebrates (including humans), there is a loss of regulation of the storage of triglycerides in adipose cells, such that the body mass of fat can increase to 30%.

Classical parabiotic2 studies conducted in the early 1970s suggested that genetically obese mice lacked a

2 Parabiosis: In a parabiotic experiment, the circulatory system of one animal is connected to a second animal. Thus, Coleman [Diabe-tologia 9, 294 (1973)] indirectly connected the circulatory system of adult ob/ob (obese) mice to that of normal mice, and the ob/ob mice lost weight; this suggested the existence of a weight-regulatory substance in the serum of the normal mice, i.e., a hormone associated with the maintenance of a normal dietary caloric intake.

IAPP KCNTATCATQRLANF LVHSSNNFGA I LSSTNVGSN TY-COOH

CGRP-I ACDTATCVTHR LA G_L L S_R S G GVVKNNFVP T N V G S K AF-COOH

CGRP-II ACNTATCVTHR LA G_L L S_R S G GMVKSNFVP T N V G S K AF-COOH

FIGURE 7-13 Comparison of the amino acid sequences of human islet amyloid polypeptide (IAPP) and calcitonin gene-related peptide (CGRP). The underlining indicates substitution of different amino acids in CGRP-I and CGRP-II as compared with IAPP. [Abstracted from Nishi, M„ Sanke, T„ Nagamatsu, S., Bell, G. I., and Steiner, D. F. (1990). Islet amyloid polypeptide—A new /3 cell secretory product related to islet amyloid deposits. /. Biol. Chem. 265, 4173-4176.]

blood-borne factor (i.e., a hormone) that regulated, via appetite control, the stimulation of glycolysis and thus the extent of body fat deposition. Also, it is known that mutations in the obese gene in the C57BL/6 mouse result in the onset of obesity, which includes increased deposition of body fat, hyperglycemia, and hyperinsu-linemia (similar to type II diabetes).

These observations led in 1995, via molecular biology techniques, to the biochemical and biological characterization of a new hormone, termed leptin.3 Leptin is a 16-kDa protein that is the plasma form of the gene product encoded by the ob gene. Daily administration of recombinant leptin to obese mice reduced their body weight by 30% within 2 weeks; in addition, leptin reduced the food intake and increased the ob/ob mouse expenditure of metabolic energy. A full understanding of the endocrinology of leptin and its potential application to the regulation of body weight will be an area of intense research activity in the near future.

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