The disruption to glucose homeostasis upon glucocorticoid (GC) treatment in adult male rats has not been fully characterized in older rats or in females. Thus, we evaluated the age- and gender-related changes in glucose homeostasis in GC-treated rats. We injected male and female rats at 3 months and 12 months of age with either dexamethasone (1.0 mg/kg body mass, intraperitoneally) or saline, daily for 5 days. All of the GC-treated rats had decreased body mass and food intake, and adrenal hypotrophy. Increased glycemia was observed in all of the GC-treated groups and only the 3-month-old female rats were not glucose intolerant. Dexamethasone treatment resulted in hyperinsulinemia and hypertriacylglyceridemia in all of the GC-treated rats. The glucose-stimulated insulin secretion (GSIS) was higher in all of the dexamethasone-treated animals, but it was less pronounced in the older animals. The β-cell mass was increased in the younger male rats treated with dexamethasone. We conclude that dexamethasone treatment induces glucose intolerance in both the 3- and 12-month-old male rats as well as hyperinsulinemia and augmented GSIS. Three-month-old female rats are protected from glucose intolerance caused by GC, whereas 12-month-old female rats developed the same complications that were present in 3- and 12-month-old male rats.

Pancreatic islet beta cells are essential for maintaining glucose homeostasis. To understand the impact of aging on beta cells, we performed meta-analysis of single-cell RNA sequencing datasets, transcription factor (TF) regulon analysis, high-resolution confocal microscopy, and measured insulin secretion from nondiabetic donors spanning most of the human life span. This revealed the range of molecular and functional changes that occur during beta cell aging, including the transcriptional deregulation that associates with cellular immaturity and reorganization of beta cell TF networks, increased gene transcription rates, and reduced glucose-stimulated insulin release. These alterations associate with activation of endoplasmic reticulum (ER) stress and autophagy pathways. We propose that a chronic state of ER stress undermines old beta cell structure function to increase the risk of beta cell failure and type 2 diabetes onset as humans age.

Glucocorticoid (GC) excess alters glucose homeostasis and promotes modifications in murinometric and anthropometric parameters in rodents and humans, respectively. β-hydroxy-β-methylbutyrate (HMB), a leucine metabolite, has been proposed as a nutritional strategy for preventing muscle wasting, but few data regarding its effects on glucose homeostasis are available. Here, we analyzed whether the effects of GC excess on glucose homeostasis may be attenuated or exacerbated by the concomitant ingestion of HMB. Adult Wistar rats (90-days-old) were assigned to four groups: (1) vehicle treated (Ctl), (2) dexamethasone (DEX) treated (Dex), (3) HMB treated (Hmb), and (4) DEX plus HMB treated (DexHmb). Dex groups received DEX (1 mg·kg body weight (BW)(-1), intraperitoneal) for 5 consecutive days. HMB groups ingested HMB (320 mg·kg BW(-1), oral gavage) for the same 5 days. HMB ingestion did not attenuate the effects of DEX on food intake and body weight loss, changes in masses of several organs, insulin resistance, and glucose intolerance (p > 0.05). In fact, in DexHmb rats, there was increased fasting glycemia and exacerbated glucose intolerance with the main effect attributed to DEX treatment (p < 0.05). HMB exerted no attenuating effect on plasma triacylglycerol levels from DexHmb rats, but it seems to attenuate the lipolysis induced by β-adrenergic stimulation (20 μmol·L(-1) isoproterenol) in fragments of retroperitoneal adipose tissue from DexHmb rats. Therefore, HMB does not attenuate the diabetogenic characteristics of GC excess. In fact, the data suggest that HMB may exacerbate GC-induced glucose intolerance.

Sepsis is associated with high mortality. Both critically ill humans and animal models of sepsis exhibit changes in their glucose homeostasis, that is, hypoglycaemia, with the progression of infection. However, the relationship between basal glycaemia, glucose tolerance and insulin sensitivity is not well understood. Thus, we aimed to evaluate this glucose homeostasis triad at the late stage of sepsis (24 h after surgery) in male Swiss mice subjected to lethal and sublethal sepsis by the caecal ligation and puncture (CLP) model. The percentage of survival 24 h after CLP procedure in the Lethal and Sublethal groups was around 66% and 100% respectively. Both Lethal and Sublethal groups became hypoglycaemic in fasting and fed states 24 h after surgery. The pronounced fed hypoglycaemia in the Lethal group was not due to worsening anorexic behaviour or hepatic inability to deliver glucose in relation to the Sublethal group. Reduction in insulin sensitivity in CLP mice occurred in a lethality-dependent manner and was not associated with glucose intolerance. Analysis of oral and intraperitoneal glucose tolerance tests, as well as the gastrointestinal motility data, indicated that CLP mice had reduced intestinal glucose absorption. Altogether, we suggest cessation of appetite and intestinal glucose malabsorption are key contributors to the hypoglycaemic state observed during experimental severe sepsis.

BackgroundGlucocorticoid excess is commonly associated with diabetogenic effects, including insulin resistance and glucose intolerance. The effects of the long-term glucagon-like peptide 1 receptor agonist treatment on the metabolic syndrome-like conditions are not yet fully elucidated. Thus, we aimed to test whether long-term liraglutide treatment could be effective as a therapy to counteract the metabolic dysfunctions induced by chronic glucocorticoid exposure.MethodsMice were given corticosterone or vehicle via their drinking water for five consecutive weeks. In addition, mice were treated with once-daily injections of either PBS or liraglutide.ResultsLiraglutide treatment slowed progression towards obesity and ectopic fat deposition in liver that otherwise occurred in corticosterone-treated mice. The drug reduced the increment in serum insulin caused by corticosterone, but did not affect the reduction of insulin sensitivity. Furthermore, liraglutide improved glucose control in mice exposed to corticosterone as evident by a delay in the progression towards post-prandial hyperglycemia and enhanced glucose clearance during a glucose tolerance test. Glucose-stimulated C-peptide levels were higher in those mice that had received liraglutide and corticosterone compared to mice that had been treated with corticosterone alone, indicating a positive role of liraglutide for beta-cell function. Morphometric analysis revealed increased beta- and alpha-cell masses that were associated with more Ki67-positive islet cells in corticosterone-treated mice irrespective of whether they were co-treated with liraglutide or not. Liraglutide had no discernible effect on alpha-cell mass.ConclusionLiraglutide can be beneficial for subjects at risk of developing metabolic complications as a result of glucocorticoid excess.

Dexamethasone is an anti-inflammatory glucocorticoid that may alter glucose and lipid homeostasis when administered in high doses or for long periods of time. Omega-3 fatty acids, present in fish oil (FO), can be used as potential modulators of intermediary glucose and lipid metabolism. Herein, we evaluate the effects of FO supplementation (1 g·kg(-1) body weight (BW)) on glucose and lipid metabolism in rats treated with dexamethasone (0.5 mg·kg(-1) BW) for 15 days. Adult male Wistar rats were distributed among 4 groups: control (saline, 1 mL·kg(-1) BW and mineral oil, 1 g·kg(-1) BW), DEX (dexamethasone and mineral oil), FO (fish oil and saline), and DFO (fish oil and dexamethasone). Dexamethasone and saline were administered intraperitoneally, and fish oil and mineral oil were administered by gavage. We evaluated functional and molecular parameters of lipid and glycemic profiles at 8 days and at the end of treatment. FO supplementation increased hepatic docosahexaenoic acid (DEX: 5.6% ± 0.7%; DFO: 10.5% ± 0.8%) and eicosapentaenoic acid (DEX: 0.3% ± 0.0%; DFO: 1.3% ± 0.1%) contents and attenuated the increase of plasma triacylglycerol, total cholesterol, and non-high-density lipoprotein cholesterol concentrations in DFO rats compared with DEX rats. These effects seem not to depend on hepatic expression of insulin receptor substrate 1, protein kinase B, peroxisome proliferator-activated receptor γ coactivator 1-α, and peroxisome proliferator-activated receptor γ. There was no effect of supplementation on body weight loss, fasting glycemia, and glucose tolerance in rats treated with dexamethasone. In conclusion, we show that FO supplementation for 15 days attenuates the dyslipidemia induced by dexamethasone treatment.

4-vinilcyclohexene diepoxide (4-VCD) causes premature ovarian failure and may result in estrogen deficiency, characterizing the transition to estropause in rodents (equivalent to menopause in women). Estropause/menopause is associated with metabolic derangements such as glucose intolerance and insulin resistance. Glucocorticoids (GCs) are known to exert diabetogenic effects. Thus, we aimed to investigate whether rats with premature ovarian failure are more prone to the diabetogenic effects of GC. For this, immature female rats received daily injections of 4-VCD [160mg/kg body weight (b.w.), intraperitoneally (i.p.)] for 15 consecutive days, whereas control rats received vehicle. After 168days of the completion of 4-VCD administration, rats were divided into 4 groups: CTL-received daily injections of saline (1mL/kg, b.w., i.p.) for 5days; DEX-received daily injections of dexamethasone (1mg/kg, b.w., i.p.) for 5days; VCD-treated as CTL group; VCD+DEX-treated as DEX group. Experiments and euthanasia occurred one day after the last dexamethasone injection. 4-VCD-treated rats exhibited ovary hypotrophy and reduced number of preantral follicles (p<0.05). Premature ovarian failure had no impact on the body weight gain or food intake, but both were reduced by the effects of dexamethasone. The increase in blood glucose, plasma insulin and triacylglycerol levels as well as the reduction in insulin sensitivity caused by dexamethasone treatment was not exacerbated in the VCD+DEX group of rats. Premature ovarian failure did change neither the hepatic content of glycogen and triacylglycerol nor the glycerol release from perigonadal adipose tissue. Glucose intolerance was observed in the VCD group after an ipGTT (p<0.05), but not after an oral glucose challenge. Glucose intolerance and compensatory pancreatic β-cell mass caused by GC were not modified by ovarian failure in the VCD+DEX group. We conclude that reduced ovarian function has no major implications on the diabetogenic effects promoted by GC treatment, indicating that other factors related to aging may make rats more vulnerable to GC side effects on glucose metabolism.

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