Specific phenotypic features of subjects affected with genetic syndromes depend on peculiarities of expression of each discrete mutation and on extent of its divergence from normal physiology. In this context, and when studying the GH/IGF-I axis of subjects with two different syndromes that include severe short stature (SSS), we noticed different metabolic phenotypes in each cohort. Subjects with Laron syndrome (LS), who have GH insensitivity (GHI), display obesity, increased body fat, enhanced insulin sensitivity and diminished incidence of diabetes mellitus. Subjects with a new syndrome (NS), who have normal GH signaling, display intrauterine growth retardation (IUGR), normal to slightly elevated body fat content, insulin resistance and early onset type 2 diabetes mellitus (T2DM). In consequence, we were able to observe the clinical consequences of different GH counter-regulation status on carbohydrate metabolism, especially considering that subjects with either syndrome most likely have diminished pancreatic reserve.