Rodent models of type 2 diabetes typically exhibit elevations in plasma concentrations of both amylin and insulin (Gill and Yen, 1991; Tokuyama et al., 1993; Pieber et al., 1994). However, rodent type 2 models may differ from humans in the etiopathogenesis of diabetes. They are often characterized by extreme insulin resistance, while the human condition is characterized by a sequence of worsening insulin resistance followed by insulin secretory failure (Saad et al., 1989). This sequence in humans was apparent in cross-sectional studies (Reaven and Miller, 1968) and was also apparent in individuals whose progression into diabetes was followed longitudinally (Saad et al., 1989). Loss of glucose-mediated insulin secretion marked the transition from impaired glucose tolerance into diabetes (Swinburn et al., 1995), consistent with the idea that insulin secretion was no longer sufficient to compensate for insulin resistance.
In accordance with descriptions of insulin secretion in human type 2 diabetes (but in contrast to the pattern in most rodent models), plasma amylin concentrations and nutrient-stimulated increases in plasma concentration were reduced in diabetic patients compared to non-diabetic subjects (Enoki et al., 1992; Fineman et al., 1996; Hanabusa et al., 1992; Hartter et al., 1991; Ludvik et al., 1991, 1996; Mitsukawa et al., 1991; Rachman et al., 1996; Sanke et al., 1991; van Jaarsveld et al., 1993). The only exception appeared to be gestational diabetes mellitus (Kautzky-Willer et al., 1996b; Zweers et al., 1992), which may be more mechanistically aligned with the severe insulin resistance of rodent type 2 models.
Thus, in humans, both type 1 diabetes mellitus and the later stages of type 2 diabetes mellitus are characterized by deficiency of both insulin and amylin secretion. It appears that severity of b-cell secretory failure correlates with severity of amylin deficiency. This concordance of deficiencies in amylin and insulin secretion observed with the progression of diabetes mellitus is consistent with their co-localization in pancreatic b-cells.
In human type 2 diabetes, fasting and stimulated plasma amylin concentrations are generally lower in those treated with insulin (typically exhibiting greater b-cell failure) than in those treated with oral hypoglycemic agents. In patients with insulin-treated type 2 diabetes, fasting concentrations were 1.8 pM (Czyzyk et al., 1996), 2.1 pM (Hartter et al., 1991), and 2.7 pM (van Jaarsveld et al., 1993), and showed only a small increase upon stimulation (Koda et al., 1992), for example, to 2.3 pM (Czyzyk et al., 1996) or 6.1 pM (van Jaarsveld et al., 1993). In comparison, patients treated for type 2 diabetes with oral hypoglycemic agents had fasting plasma amylin concentrations that were somewhat higher (e.g., 4.8 pM, Hartter et al., 1991; 5.7 pM, van Jaarsveld et al., 1993; and 3.2 pM, Czyzyk et al., 1996) that became higher upon stimulation (e.g., to 9.4 pM, van Jaarsveld et al., 1993, and 9.8 pM, Czyzyk et al., 1996).
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