The role of phacoemulsification surgery in the incidence rate of rhegmatogenous retinal detachment.

PURPOSE: To investigate changes in the incidence rate of primary rhegmatogenous retinal detachment (RRD) surgery over time and to determine to what extent these changes can be attributed to pseudophakia. METHODS: This nationwide cohort study was based on national patient registries. The study population comprised individuals at risk of RRD aged 40 years and above from 2006 to 2021 in Denmark. The primary outcome was RRD incidence, and the exposure was phacoemulsification surgery. A chart review was conducted to validate and examine the lens status of the outcome. RESULTS: The crude and age-adjusted incidence rate of RRD in the Danish population increased significantly during the study period. The largest increase in RRD was seen in phakic RRD (phRRD) (65%), whereas pseudophakic RRD (pRRD) accounted for 35% of the total increase. A chart review revealed that 17% of phRRDs were misclassified as pseudophakic, resulting in pRRD accounting for a total of 45% of the increase in RRD. The prevalence of pseudophakia in Denmark grew significantly for all age groups and for both sexes (p = 10-6) from 2006 to 2021, but the 1-year incidence of pRRD in the pseudophakic population was constant throughout the entire period. CONCLUSION: The incidence rate of RRD is continuing to increase in Denmark. The increase in phRRD remains undetermined, and while the risk of pRRD seemed to be constant during the study period, 45% of the overall increase in RRD could be attributed to the rise of a growing pseudophakic population.

Whole-Body and Forearm Muscle Protein Metabolism in Patients With Acromegaly Before and After Treatment.

BACKGROUND: Active acromegaly is characterized by increased lean body mass, but the mechanisms underlying the protein anabolic effect are unclear. AIM: To study if active acromegaly induces reversible changes in whole-body and skeletal muscle protein kinetics. PATIENTS AND METHODS: Eighteen patients with acromegaly were investigated before and 47 ± 10 weeks after disease control by surgery (n = 8) and/or medical treatment (n = 10). Labeled phenylalanine and tyrosine tracers were employed to assess whole-body and regional forearm muscle protein kinetics. Intramyocellular protein signaling was assessed in skeletal muscle biopsies, and whole-body dual-energy X-ray absorptiometry scan and indirect calorimetry assessed lean body mass (LBM) and resting energy expenditure, respectively. RESULTS: Disease control induced a 7% decrease in lean body mass (P < .000) and a 14% decrease in LBM-adjusted energy expenditure. Whole-body phenylalanine breakdown decreased after disease control (P = .005) accompanied by a decrease in the degradation of phenylalanine to tyrosine (P = .005) and a decrease in whole-body phenylalanine synthesis (P = .030). Skeletal muscle protein synthesis tended to decrease after disease control (P = .122), whereas the muscle protein breakdown (P = .437) and muscle protein loss were unaltered (P = .371). Unc-51 like autophagy activating kinase 1 phosphorylation, an activator of protein breakdown, increased after disease control (P = .042). CONCLUSIONS: Active acromegaly represents a reversible high flux state in which both whole-body protein breakdown and synthesis are increased, whereas forearm muscle protein kinetics are unaltered. Future studies are needed to decipher the link between protein kinetics and the structure and function of the associated growth hormone-induced increase in lean body mass.

Ketone Body Infusion Abrogates Growth Hormone-Induced Lipolysis and Insulin Resistance.

CONTEXT: Exogenous ketone body administration lowers circulating glucose levels but the underlying mechanisms are uncertain. OBJECTIVE: We tested the hypothesis that administration of the ketone body ß-hydroxybutyrate (ßOHB) acutely increases insulin sensitivity via feedback suppression of circulating free fatty acid (FFA) levels. METHODS: In a randomized, single-blinded crossover design, 8 healthy men were studied twice with a growth hormone (GH) infusion to induce lipolysis in combination with infusion of either ßOHB or saline. Each study day comprised a basal period and a hyperinsulinemic-euglycemic clamp combined with a glucose tracer and adipose tissue and skeletal muscle biopsies. RESULTS: ßOHB administration profoundly suppressed FFA levels concomitantly with a significant increase in glucose disposal and energy expenditure. This was accompanied by a many-fold increase in skeletal muscle content of both ßOHB and its derivative acetoacetate. CONCLUSION: Our data unravel an insulin-sensitizing effect of ßOHB, which we suggest is mediated by concomitant suppression of lipolysis.

Reversible insulin resistance in muscle and fat unrelated to the metabolic syndrome in patients with acromegaly.

BACKGROUND: Patients with active acromegaly exhibit insulin resistance despite a lean phenotype whereas controlled disease improves insulin sensitivity and increases fat mass. The mechanisms underlying this paradox remain elusive, but growth hormone (GH)-induced lipolysis plays a central role. The aim of the study was to investigative the molecular mechanisms of insulin resistance dissociated from obesity in patients with acromegaly. METHODS: In a prospective study, twenty-one patients with newly diagnosed acromegaly were studied at diagnosis and after disease control obtained by either surgery alone (n=10) or somatostatin analogue (SA) treatment (n=11) with assessment of body composition (DXA scan), whole body and tissue-specific insulin sensitivity and GH and insulin signalling in adipose tissue and skeletal muscle. FINDINGS: Disease control of acromegaly significantly reduced lean body mass (p<0.001) and increased fat mass (p<0.001). At diagnosis, GH signalling (pSTAT5) was constitutively activated in fat and enhanced expression of GH-regulated genes (CISH and IGF-I) were detected in muscle and fat. Insulin sensitivity in skeletal muscle, liver and adipose tissue increased after disease control regardless of treatment modality. This was associated with enhanced insulin signalling in both muscle and fat including downregulation of phosphatase and tensin homolog (PTEN) together with reduced signalling of GH and lipolytic activators in fat. INTERPRETATION: In conclusion, the study support that uncontrolled lipolysis is a major feature of insulin resistance in active acromegaly, and is characterized by upregulation of PTEN and suppression of insulin signalling in both muscle and fat. FUNDING: This work was supported by a grant from the Independent Research Fund, Denmark (7016-00303A) and from the Alfred Benzon Foundation, Denmark.

Fibroblast Activation Protein is a GH Target: A Prospective Study of Patients with Acromegaly Before and After Treatment.

BACKGROUND: Fibroblast growth factor 21 (FGF21) is a circulating hormone with pleiotropic metabolic effects, which is inactivated by fibroblast activation protein (FAP). Data regarding interaction between FGF21, FAP, and growth hormone (GH) are limited, but it is noteworthy that collagens are also FAP substrates, since GH potently stimulates collagen turnover. AIM: To measure circulating FGF21 components, including FAP, in patients with acromegaly before and after disease control. METHODS: Eighteen patients with active acromegaly were studied at the time of diagnosis and ≥ 6 months after disease control by either surgery or medical treatment. Serum levels of total and active FGF21, ß-klotho, FAP, and collagen turnover markers were measured by immunoassays. Expression of putative FGF21-dependent genes were measured in adipose tissue by reverse transcriptase-polymerase chain reaction, body composition assessed by dual-energy x-ray absorptiometry scan, and insulin sensitivity estimated with homeostatic model assessment of insulin resistance (HOMA-IR). RESULTS: Total FGF21, active FGF21 and ß-klotho remained unchanged. Insulin sensitivity and body fat mass increased after disease control but neither correlated with active FGF21. Expression of FGF21-dependent genes did not change after treatment. FAP levels (µg/L) were markedly reduced after treatment [105.6 ± 29.4 vs 62.2 ± 32.4, P < 0.000]. Collagen turnover markers also declined significantly after treatment and ΔFAP correlated positively with ΔProcollagen Type I (P < 0.000) and Type III (P < 0.000). CONCLUSION: 1) Circulating FGF21 and ß-klotho do not change in response to acromegaly treatment, 2) FAP concentrations in serum decrease after disease control and correlate positively with collagen turnover markers, and 3) FAP is a hitherto unrecognized GH target linked to collagen turnover. CLINICAL TRIALS REGISTRATION: NCT00647179.

Growth hormone signaling and action in obese versus lean human subjects.

Growth hormone (GH) levels are blunted in obesity, but it is not known whether this relates to altered GH sensitivity and whether this influences the metabolic adaptation to fasting. Therefore, we investigated the effect of obesity on GH signal transduction and fasting-induced changes in GH action. Nine obese (BMI 35.7 kg/m2) and nine lean (BMI 21.5 kg/m2) men were studied in a randomized crossover design with 1) an intravenous GH bolus, 2) an intravenous saline bolus, and 3) 72 h of fasting. Insulin sensitivity (hyperinsulinemic, euglycemic clamp) and substrate metabolism (glucose tracer and indirect calorimetry) were measured in studies 1 and 2. In vivo GH signaling was assessed in muscle and fat biopsies. GH pharmacokinetics did not differ between obese and lean subjects, but endogenous GH levels were reduced in obesity. GH signaling (STAT5b phosphorylation and CISH mRNA transcription), and GH action (induction of lipolysis and peripheral insulin resistance) were similar in the two groups, but a GH-induced insulin antagonistic effect on endogenous glucose production only occurred in the obese. Fasting-induced IGF-I reduction was completely abrogated in obese subjects despite a comparable relative increase in GH levels (ΔIGF-I: lean, -66 ± 10 vs. obese, 27 ± 16 µg/l; P < 0.01; ΔGH: lean, 647 ± 280 vs. obese, 544 ± 220%; P = 0.76]. We conclude that 1) GH signaling is normal in obesity, 2) in the obese state, the preservation of IGF-I with fasting and the augmented GH-induced central insulin resistance indicate increased hepatic GH sensitivity, 3) blunted GH levels in obesity may protect against insulin resistance without compromising IGF-I status.