Clustering of cardio-metabolic risk factors in parents of adolescents with type 1 diabetes and microalbuminuria

Objective To evaluate the association between a clustering of cardio-metabolic risk factors in parents and the development of microalbuminuria (MA) in their offspring with childhood-onset type 1 diabetes (T1D). Methods The study population comprised 53 parents (mean age [±SD]: 56.7±6.2 years) of 35 T1D young people with MA (MA+) and 86 parents (age: 56.1±6.3 years) of 50 matched offspring with normoalbuminuria (MA–), who underwent clinical, biochemical and cardiovascular imaging assessments. The primary study endpoint was the difference between parents from the MA+ and MA− groups in a cardio-metabolic risk score, calculated as the average value of the standardized measures (z-scores) for waist circumference, blood pressure, fasting glucose, insulin, HDL-cholesterol and triglycerides levels. Cardiovascular parameters, including carotid intima-media thickness (cIMT), flow-mediated dilatation (FMD) and pulse wave velocity (PWV), were also assessed. A DXA scan was performed to assess body composition. Results The cardio-metabolic risk score was significantly higher in parents of MA+ compared to parents of MA− offspring (mean [95% CI]: 1.066[0.076; 2.056] vs −0.268[−0.997; 0.460], P = .03). Parents of MA+ offspring had slightly higher values of waist circumference, lipids, insulin and blood pressure, although only diastolic blood pressure was statistically different between the 2 groups (P = .0085). FMD, cIMT, PWV (all P > .3), and DXA parameters (all P > .2) were not significantly different between the 2 groups. Conclusions Parents of young offspring with childhood-onset T1D and MA showed an abnormal metabolic profile, reflected by a calculated risk score. The finding supports the role of a familial predisposition to risk of developing diabetic nephropathy.The study was supported by a grant from Diabetes UK (09/0003859). P.H.T. was financially supported by Academy of Finland (decision 130171); The Diabetes Research Foundation, Finland; Foundation for Pediatric Research, Finland; The Alma and K. A. Snellman Foundation, Oulu, Finland; and The Finnish Medical Foundation

Clustering of cardio-metabolic risk factors in parents of adolescents with type 1 diabetes and microalbuminuria

OBJECTIVE: To evaluate the association between a clustering of cardio‐metabolic risk factors in parents and the development of microalbuminuria (MA) in their offspring with childhood‐onset type 1 diabetes (T1D). METHODS: The study population comprised 53 parents (mean age [±SD]: 56.7±6.2 years) of 35 T1D young people with MA (MA+) and 86 parents (age: 56.1±6.3 years) of 50 matched offspring with normoalbuminuria (MA–), who underwent clinical, biochemical and cardiovascular imaging assessments. The primary study endpoint was the difference between parents from the MA+ and MA− groups in a cardio‐metabolic risk score, calculated as the average value of the standardized measures (z‐scores) for waist circumference, blood pressure, fasting glucose, insulin, HDL‐cholesterol and triglycerides levels. Cardiovascular parameters, including carotid intima‐media thickness (cIMT), flow‐mediated dilatation (FMD) and pulse wave velocity (PWV), were also assessed. A DXA scan was performed to assess body composition. RESULTS: The cardio‐metabolic risk score was significantly higher in parents of MA+ compared to parents of MA− offspring (mean [95% CI]: 1.066[0.076; 2.056] vs −0.268[−0.997; 0.460], P = .03). Parents of MA+ offspring had slightly higher values of waist circumference, lipids, insulin and blood pressure, although only diastolic blood pressure was statistically different between the 2 groups (P = .0085). FMD, cIMT, PWV (all P > .3), and DXA parameters (all P > .2) were not significantly different between the 2 groups. CONCLUSIONS: Parents of young offspring with childhood‐onset T1D and MA showed an abnormal metabolic profile, reflected by a calculated risk score. The finding supports the role of a familial predisposition to risk of developing diabetic nephropathy

Two-site recognition of Staphylococcus aureus peptidoglycan by lysostaphin SH3b

Lysostaphin is a bacteriolytic enzyme targeting peptidoglycan, the essential component of the bacterial cell envelope. It displays a very potent and specific activity toward staphylococci, including methicillin-resistant Staphylococcus aureus. Lysostaphin causes rapid cell lysis and disrupts biofilms, and is therefore a therapeutic agent of choice to eradicate staphylococcal infections. The C-terminal SH3b domain of lysostaphin recognizes peptidoglycans containing a pentaglycine crossbridge and has been proposed to drive the preferential digestion of staphylococcal cell walls. Here we elucidate the molecular mechanism underpinning recognition of staphylococcal peptidoglycan by the lysostaphin SH3b domain. We show that the pentaglycine crossbridge and the peptide stem are recognized by two independent binding sites located on opposite sides of the SH3b domain, thereby inducing a clustering of SH3b domains. We propose that this unusual binding mechanism allows synergistic and structurally dynamic recognition of S. aureus peptidoglycan and underpins the potent bacteriolytic activity of this enzyme

Short-term administration of pegvisomant improves hepatic insulin sensitivity and reduces soleus muscle intramyocellular lipid content in young adults with type 1 diabetes.

Context: Data on metabolic effects of Growth Hormone (GH) derived from studies using GH suppression by pharmacological agents may not reflect selective actions. Objective: To evaluate the effects of GH antagonism on glucose and lipid metabolism using pegvisomant, a selective GH receptor antagonist in patients with type 1 diabetes (T1D). Design & participants: In a randomised, placebo-controlled, crossover study, 10 young adults with T1D were evaluated at baseline, and after 4 weeks of treatment with either 10mg of pegvisomant or placebo. The assessments included an overnight euglycaemic steady state followed by a hyperinsulinaemic euglycaemic clamp, and employed glucose and glycerol cold stable isotopes. Outcome measures: Hepatic and peripheral insulin sensitivity (IS), lipid turnover and intramyocellular lipid (IMCL) Results: Compared with placebo, pegvisomant treatment resulted in lower IGF-I levels (p<0.001). During the overnight steady state, insulin requirements for euglycaemia (p=0.019), insulin levels (p=0.008) and glucose production rates (Ra) (p=0.033) were reduced. During the clamp study, glucose infusion rates (p=0.031) increased, glucose Ra (p=0.015) decreased whilst glucose disposal rates were unchanged. Free fatty acids (FFA) levels were similar during the steady state, but were lower during the clamp (p=0.040) following pegvisomant. Soleus muscle IMCL decreased following treatment (p=0.024), however no change in tibialis anterior muscle was observed. Conclusions: The study demonstrates that GH antagonism in T1D results in improved hepatic IS. Lack of consistent changes in FFA may suggest a direct effect of GH on IS. Unchanged peripheral IS despite reductions in IMCL indicate that GH induced alterations in IMCL may not be causally linked to glucose metabolism

Short-term administration of pegvisomant improves hepatic insulin sensitivity and reduces soleus muscle intramyocellular lipid content in young adults with type 1 diabetes.

Context: Data on metabolic effects of Growth Hormone (GH) derived from studies using GH suppression by pharmacological agents may not reflect selective actions. Objective: To evaluate the effects of GH antagonism on glucose and lipid metabolism using pegvisomant, a selective GH receptor antagonist in patients with type 1 diabetes (T1D). Design & participants: In a randomised, placebo-controlled, crossover study, 10 young adults with T1D were evaluated at baseline, and after 4 weeks of treatment with either 10mg of pegvisomant or placebo. The assessments included an overnight euglycaemic steady state followed by a hyperinsulinaemic euglycaemic clamp, and employed glucose and glycerol cold stable isotopes. Outcome measures: Hepatic and peripheral insulin sensitivity (IS), lipid turnover and intramyocellular lipid (IMCL) Results: Compared with placebo, pegvisomant treatment resulted in lower IGF-I levels (p<0.001). During the overnight steady state, insulin requirements for euglycaemia (p=0.019), insulin levels (p=0.008) and glucose production rates (Ra) (p=0.033) were reduced. During the clamp study, glucose infusion rates (p=0.031) increased, glucose Ra (p=0.015) decreased whilst glucose disposal rates were unchanged. Free fatty acids (FFA) levels were similar during the steady state, but were lower during the clamp (p=0.040) following pegvisomant. Soleus muscle IMCL decreased following treatment (p=0.024), however no change in tibialis anterior muscle was observed. Conclusions: The study demonstrates that GH antagonism in T1D results in improved hepatic IS. Lack of consistent changes in FFA may suggest a direct effect of GH on IS. Unchanged peripheral IS despite reductions in IMCL indicate that GH induced alterations in IMCL may not be causally linked to glucose metabolism