What the Genetics of Lipodystrophy Can Teach Us About Insulin Resistance and Diabetes

Abstract

Genetic lipodystrophic syndromes are rare diseases characterized by generalized or partial fat atrophy (lipoatrophy) associated with severe metabolic complications such as insulin resistance (IR), diabetes, dyslipidemia, nonalcoholic fatty liver disease, and ovarian hyperandrogenism. During the last 15 years, mutations in several genes have been shown to be responsible for monogenic forms of lipodystrophic syndromes, of autosomal dominant or recessive transmission. Although the molecular basis of lipodystrophies is heterogeneous, most mutated genes lead to impaired adipogenesis, adipocyte lipid storage, and/or formation or maintenance of the adipocyte lipid droplet (LD), showing that primary alterations of adipose tissue (AT) can result in severe systemic metabolic and endocrine consequences. The reduced expandability of AT alters its ability to buffer excess caloric intake, leading to ectopic lipid storage that impairs insulin signaling and other cellular functions ("lipotoxicity"). Genetic studies have also pointed out the close relationships between ageing, inflammatory processes, lipodystrophy, and IR.

Risk of diabetes in HIV‐infected patients is associated with cirrhosis but not with chronic HCV coinfection in a French nationwide HIV cohort

“…Both HIV and hepatitis C (HCV) infections have been associated with a higher risk of diabetes mellitus (DM), but results are conflicting . In HIV‐infected patients, insulin resistance (IR) and DM have been related to lipodystrophy and exposure to the first generation of protease inhibitors (PI) or to D‐thymidine nucleoside analogues and didanosine . In HCV‐infected patients, apart from cirrhosis from any cause, which is a well established risk factor for IR and DM, it has been suggested that HCV infection could directly induce IR and DM by interfering with glucose metabolism .…”

Glucagon-like peptide-1 analogues - an efficient therapeutic option for the severe insulin resistance of lipodystrophic syndromes: two case reports

“…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].…”

“…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].…”

“…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.…”

One‐year metreleptin improves insulin secretion in patients with diabetes linked to genetic lipodystrophic syndromes

“…Patients with diabetes, attributable to familial partial lipodystrophy linked to LMNA (nine women), PPARG (one man) or PLIN1 mutations (one woman), or to congenital generalized lipodystrophy attributable to AGPAT2 mutations (four women, one man), were included in the study (Table S1). The patients presented with different forms of lipodystrophic syndromes, with insulin resistance and dyslipidaemia attributable to previously described causative mutations . Their age and BMI were 39.2 ± 4.0 years and 23.9 ± 0.7 kg/m 2 , respectively.…”