Lipodystrophic syndromes are rare disorders characterized by selective loss of adipose tissue, mainly from subcutaneous compartments. Lipoatrophy may vary from being partial, co-existing with adipose tissue depots in ectopic sites, to generalized [
1]. These syndromes are usually linked with severe metabolic complications, such as insulin resistance, diabetes mellitus, dyslipidemia, hepatic steatosis, and hypertension [
2,
3]. Loss of adipose tissue seems to give rise to both lipodystrophy and metabolic disorders [
2], which suggests that it is the absence of fat tissue and the consequent leptin deficiency that leads to insulin resistance [
4,
5]. Furthermore, adipocytes provide a benign location to accumulate lipids and, thus, when they are absent, lipids will store in the liver, muscle, and ectopic tissues, causing significant metabolic complications [
6]. Patients may present acanthosis nigricans, acromegaloid features, muscular hypertrophy, and hirsutism in the context of ovarian hyperandrogenism: polycystic ovary syndrome (PCOS) [
2,
7]. Over the last decades, several causative genetic mutations have been identified in patients with lipodystrophies. Nevertheless, lipodystrophy is a clinical diagnosis which is based on a physical examination, and many such patients present no mutations of identified genes, suggesting that other genes are involved and have not yet been deciphered [
8]. The treatment of complications involves classical intervention strategies, however, owing to the severity of insulin resistance, managing such complications can be challenging. Glucagon-like peptide-1 (GLP-1) analogues stimulate glucose-dependent insulin secretion and suppress inappropriately elevated glucagon secretion, thus improving glucose homeostasis. These analogues also delay gastric emptying and act centrally to promote satiety, thus reducing food intake, which leads to weight loss. This loss seems to result from a reduction in fat mass, rather than lean tissue mass [
9], with a preferential decrease in visceral fat [
10]. We describe two clinical cases of diabetes in patients with lipodystrophic features who were successfully treated with GLP-1 analogues.