Continuous Glucose Monitoring-Recorded Hypoglycemia with Insulin Degludec or Insulin Glargine U100 in People with Type 1 Diabetes Prone to Nocturnal Severe Hypoglycemia.

Background and Aims: Nocturnal hypoglycemia is mainly a consequence of inappropriate basal insulin therapy in type 1 diabetes (T1D) and may compromise optimal glycemic control. Insulin degludec is associated with a lower risk of nocturnal hypoglycemia in T1D. As nocturnal hypoglycemia is often asymptomatic, we applied continuous glucose monitoring (CGM) to detect a more precise occurrence of nocturnal hypoglycemia in the HypoDeg trial, comparing insulin degludec with insulin glargine U100 in people with T1D and previous nocturnal severe hypoglycemia. Materials and Methods: In the HypoDeg trial, 149 people with T1D were included in an open-label randomized cross-over trial. Sixty-seven participants accepted optional participation in the predefined substudy of 4 × 6 days of blinded CGM requiring completion of at least one CGM period in each treatment arm. CGM data were reviewed for hypoglycemic events. Results: Treatment with insulin degludec resulted in a relative rate reduction (RRR) of 36% (95% confidence interval [CI]: 10%-54%; P < 0.05) in nocturnal CGM-recorded hypoglycemia (≤3.9 mmol/L), corresponding to an absolute rate reduction (ARR) of 0.85 events per person-week. In nocturnal CGM-recorded hypoglycemia (≤3.0 mmol/L), we found an RRR of 53% (95% CI: 36%-65%; P < 0.001), corresponding to an ARR of 0.75 events per person-week. At the lower detection limit of the CGM (≤2.2 mmol/L), treatment with insulin degludec resulted in a significant RRR of 58% (95% CI: 23%-77%; P = 0.005). The reductions were primarily due to significant RRRs in asymptomatic hypoglycemia. Conclusion: In people with T1D, prone to nocturnal severe hypoglycemia, insulin degludec compared with insulin glargine U100 significantly reduces nocturnal CGM-recorded hypoglycemia. www.clinicaltrials.gov (#NCT02192450).

FGF21 and glycemic control in patients with T1D.

PURPOSE: Fibroblast growth factor (FGF) 21 is a circulating hormone with an important role in metabolic regulation. FGF21 production in humans responds positively to glucose consumption and we hypothesize that serum FGF21 concentration is associated to glycemic control. METHODS: We enrolled 31 patients with type 1 diabetes (T1D) based on their HbA1c (well-regulated (HbA1c <53 mmol/mol), (n = 18) or poorly-regulated (HbA1c >69 mmol/mol), (n = 13). Twelve patients (39%) were diagnosed with retinopathy. Twenty healthy individuals comparable for age and gender distribution were included as a reference group. Serum FGF21, intact FGF21, fibroblast activation protein (FAP), adiponectin, and C-Reactive Protein (CRP) were measured by immunoassays. RESULTS: No correlation between FGF21 concentration and HbA1c was found. Patients with T1D had lower levels of circulating FGF21 as compared with the reference group, but the difference was nonsignificant (p = 0.12). Dividing the patients according to retinopathy, we found that T1D patients with retinopathy had significantly lower FGF21 concentrations (10.0 ng/L) as compared with the healthy reference group (37.1 ng/L), (p = 0.02). We found significantly higher levels of the FGF21 cleaving enzyme, FAP, in patients with T1D (97.2 µg/L) as compared with the healthy control group (78.5 µg/L), (p = 0.006). Interestingly, serum FAP levels correlated significantly with circulating FGF21 levels in T1D patients, but this correlation was not found in the healthy controls. CONCLUSIONS: We found no association between circulating FGF21 levels and HbA1c. T1D patients with retinopathy had significantly lower FGF21 levels as compared with healthy individuals, but it remains unclear if the lower levels of FGF21 are pathogenically related to the development of microvascular complications. Of note, serum FAP levels were significantly higher in all T1D patients as compared with the healthy individuals.

Smad2 Phosphorylation in Diabetic Kidney Tubule Epithelial Cells Is Associated with Modulation of Several Transforming Growth Factor-ß Family Members.

BACKGROUND: The role of transforming growth factor-ß (TGF-ß) has recently gained much attention in diabetic nephropathy and kidney fibrosis. In this study, we extend this to an assessment of transcriptional regulation of the entire TGF-ß superfamily in kidneys from diabetic vs. healthy mice. In order to study the translation between mouse model and patients, we evaluated the signature of phosphorylated Sma- and Mad-related protein 2 (pSmad2), as molecular marker of TGF-ß/activin activity, in the kidneys of streptozotocin (STZ)-treated mice compared to that of type 1 diabetes (T1D) patients. METHODS: Patterns of pSmad2 were determined in kidneys from T1D patients with progressed diabetic nephropathy (DN), defined by hyperglycemia, microalbuminuria, and increased levels of serum creatinine. They were compared to changes seen in the STZ-induced DN mouse model. This was studied by immunohistochemistry (IHC) with an antibody specific for pSmad2. Diabetic mice were also characterized by pSmad1/5/8 (IHC), pSmad2/3 (flow cytometry), and TGF-ß family members including bone morphogenetic protein (BMP)-like proteins (quantitative real-time polymerase chain reaction [qPCR]). RESULTS: Renal tubules in DN patients and in STZ mice showed upregulation of pSmad2 concomitant with significantly enlarged distal tubule lumens (p < 0.0001). Renal-derived CD11b+ cells from STZ mice showed elevated pSmad2/3, while endothelial cells had reduced pSmad2/3 levels. No pSmad1/5/8 was observed in the tubule compartment of STZ-treated mice. On total kidney mRNA level, a signature favoring activation of the TGF-ß/activin pathway and inhibition of the BMP pathway was demonstrated by qPCR. CONCLUSION: Although the pre-clinical DN model lacks the features of fibrosis present in human DN, both species show induction of a local milieu favoring pSmad2 signaling, which may be useful as a disease biomarker in pre-clinical models.