Male FATZO mice spontaneously develop significant metabolic disease when compared to normal controls while maintaining hyperglycemia in the presence of high leptin levels and hyperinsulinemia.
These results identify a novel molecular pathway by which leptin confers inhibitory action on insulin secretion, and impaired PP-1 inhibition by leptin may be involved in dysfunction of the adipoinsular axis during the development of hyperinsulinemia and type 2 diabetes mellitus.
Subsequently, in vitro studies in 3T3-L1 (white) and T37i (brown) adipocytes suggest that the increased leptin and adiponectin levels were mainly driven by the elevated insulin levels.
This led to metabolic consequences, with significant higher leptin levels and a trend towards hyperinsulinemia, indicating a phenotype resembling the metabolic syndrome.
To investigate the role of chronic hyperinsulinemia in the regulation of plasma leptin concentrations, we studied 13 patients with surgically confirmed insulinoma before and after tumor removal, along with 15 healthy control subjects matched for sex, age, and BMI.
In first-degree relatives normal glucose tolerant women, fasting hyperinsulinemia, independently of the presence of metabolic syndrome, is associated with elevated IL-6 and leptin levels, suggesting an increased cardiovascular risk.
This study demonstrates that targeted POMC gene delivery in the hypothalamus suppresses food intake and weight gain and reduces visceral adiposity and hyperinsulinemia in leptin-resistant obese Zucker rats.
Liver-specific AlbCre+Cc1<sup>fl/fl</sup> mutants exhibited impaired insulin clearance and hyperinsulinemia at 2 months, followed by hepatic insulin resistance (assessed by hyperinsulinemic-euglycemic clamp analysis) and steatohepatitis at ~ 7 months of age, at which point visceral obesity and hyperphagia developed, in parallel to hyperleptinemia and blunted hypothalamic STAT3 phosphorylation in response to an intraperitoneal injection of leptin.
Further, similar hypothalamic leptin transgene expression abrogated chronic hyperglycemia and hyperinsulinemia, the predisposing risk factors of the age and environmentally acquired diabetes type 2, and instituted euglycemia by independently activating relays that stimulate glucose metabolism and repress hyperinsulinemia and improve insulin sensitivity in the periphery.
Women with polycystic ovaries on ultrasound have increased insulin sensitivity and possible leptin resistance, which could predispose to future weight gain.
To that end, we conducted a double-blind, placebo-controlled study of the effects of metformin on body mass index (BMI), serum leptin, glucose tolerance, and serum lipids in obese adolescents with fasting hyperinsulinemia and a family history of type 2 diabetes.
Furthermore, hormones that affect energy homeostasis also affect sleep/wake states: the orexigenic hormone ghrelin promotes wakefulness, and the anorexigenic hormones leptin and insulin increase the duration of slow-wave sleep.
We suggest that dysregulation of the adipoinsular axis in obese individuals due to defective leptin reception by beta-cells may result in chronic hyperinsulinemia and may contribute to the pathogenesis of adipogenic diabetes.
Recently, we found that old male BN rats treated chronically with troglitazone, an insulin sensitizer, lowered high insulin and leptin levels, decreased body fat, and corrected the blunted food intake and body weight gain response to fasting without affecting basal ARC NPY gene expression.
Leptin resistance in obese individuals is frequently associated with insulin resistance and pronounced hyperinsulinaemia indicating a negative crosstalk of the insulin and leptin signalling chain.
If leptin and insulin sensitivities increase concurrently, the combined effect could be a decrease in fat mass, consistent with the fact that increasing insulin sensitivity is often associated with fat mass loss in trials.