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Davis A.K.,Benaroya Research Institute | DuBose S.N.,Jaeb Center for Health Research | Haller M.J.,University of Florida | Miller K.M.,Jaeb Center for Health Research | And 10 more authors.
Diabetes Care | Year: 2015

OBJECTIVE It is generally accepted that complete b-cell destruction eventually occurs in individuals with type 1 diabetes, which has implications for treatment approaches and insurance coverage. The frequency of residual insulin secretion in a large cohort of individuals at varying ages of diagnosis and type 1 diabetes duration is unknown. RESEARCH DESIGN AND METHODS The frequency of residual insulin secretion was determined by measurement of nonfasting serum C-peptide concentration in 919 individuals with type 1 diabetes according to prespecified groups based on age at diagnosis and duration of disease (from 3 to 81 years' duration). Stimulated C-peptide was measured in those with detectable nonfasting values and a group of those with undetectable values as control. RESULTS The overall frequency of detectable nonfasting C-peptide was 29%, decreasing with time fromdiagnosis regardless of age at diagnosis. In all duration groups, the frequency of C-peptide was higher with diagnosis age >18 years compared with £18 years. Nineteen percent of those with undetectable nonfasting C-peptide were C-peptide positive upon stimulation testing. CONCLUSIONS The American Diabetes Association's definition of type 1 diabetes as "usually leading to absolute insulin deficiency" results in clinicians often considering the presence of residual insulin secretion as unexpected in this population. However, our data suggest that residual secretion is present in almost one out of three individuals 3 ormore years fromtype 1 diabetes diagnosis. The frequency of residual C-peptide decreaseswith time from diagnosis regardless of age at diagnosis, yet at all durations of disease, diagnosis during adulthood is associated with greater frequency and higher values of C-peptide. © 2015 by the American Diabetes Association. Source

Williams R.C.,U.S. National Institute of Diabetes and Digestive and Kidney Diseases | Muller Y.L.,U.S. National Institute of Diabetes and Digestive and Kidney Diseases | Hanson R.L.,U.S. National Institute of Diabetes and Digestive and Kidney Diseases | Knowler W.C.,U.S. National Institute of Diabetes and Digestive and Kidney Diseases | And 10 more authors.
Diabetologia | Year: 2011

Aims/hypothesis: We sought to identify the physiological implications of genetic variation at the HLA-DRB1 region in full-heritage Pima Indians in Arizona. Methods: Single-nucleotide polymorphisms from the HLA region on chromosome 6p were tested for association with skeletal muscle mRNA expression of HLA-DRB1 and HLA-DRA, and with type 2 diabetes mellitus and prediabetic traits. Results: The A allele at rs9268852, which tags HLA-DRB1 02(1602), was associated both with higher HLA-DRB1 mRNA expression (n = 133, p = 4.27 × 10-14) and decreased risk of type 2 diabetes (n = 3,265, OR 0.723, p = 0.002). Among persons with normal glucose tolerance (n = 266) this allele was associated with a higher mean acute insulin response during an intravenous glucose tolerance test (p = 0.005), higher mean 30 min insulin concentration during an oral glucose tolerance test (p = 0.017) and higher body fat percentage (p = 0.010). The polymorphism was not associated with HLA-DRA mRNA expression or insulin sensitivity. Conclusions/interpretation: HLA-DRB1 02 is protective for type 2 diabetes, probably by enhancing self tolerance, thereby protecting against the autoimmune-mediated reduction of insulin secretion. © 2011 Springer-Verlag (outside the USA). Source

Albers J.J.,University of Washington | Albers J.J.,Northwest Lipid Metabolism and Diabetes Research Laboratories | Day J.R.,University of Washington | Wolfbauer G.,University of Washington | And 3 more authors.
Biochimica et Biophysica Acta - Proteins and Proteomics | Year: 2011

The plasma phospholipid transfer protein (PLTP) plays a key role in lipid and lipoprotein metabolism. It has six potential N-glycosylation sites. To study the impact of these sites on PLTP secretion and activity, six variants containing serine to alanine point mutations were prepared by site-directed mutagenesis and expressed in Chinese hamster ovary Flp-In cells. The apparent size of each of the six PLTP mutants was slightly less than that of wild type by Western blot, indicating that all six sites are glycosylated or utilized. The size of the carbohydrate at each N-glycosylation site ranged from 3.14 to 4.2 kDa. The effect of site-specific N-glycosylation removal on PLTP secretion varied from a modest enhancement (15% and 60%), or essentially no effect, to a reduction in secretion (8%, 14% and 32%). Removal of N-glycosylation at any one of the six glycosylation sites resulted in a significant 35-78% decrease in PLTP activity, and a significant 29-80% decrease in PLTP specific activity compared to wild type. These data indicate that although no single N-linked carbohydrate chain is a requirement for secretion or activity, the removal of the carbohydrate chains had a quantitative impact on cellular secretion of PLTP and its phospholipid transfer activity. © 2011 Elsevier B.V. All rights reserved. Source

Sherr J.L.,Yale University | Ruedy K.J.,Jaeb Center for Health Research | Foster N.C.,Jaeb Center for Health Research | Piche C.A.,Locemia Solutions ULC. | And 13 more authors.
Diabetes Care | Year: 2016

Objective Treatment of severe hypoglycemia outside of the hospital setting is limited to intramuscular glucagon requiring reconstitution prior to injection. The current study examined the safety and dose-response relationships of a needle-free intranasal glucagon preparation in youth aged 4 to <17 years. Research Design and Methods A total of 48 youth with type 1 diabetes completed the study at seven clinical centers. Participants in the two youngest cohorts (4 to <8 and 8 to <12 years old) were randomly assigned to receive either 2 or 3 mg intranasal glucagon in two separate sessions or to receive a single, weight-based dose of intramuscular glucagon. Participants aged 12 to <17 years received 1 mg intramuscular glucagon in one session and 3 mg intranasal glucagon in the other session. Glucagon was given after glucose was lowered to <80 mg/dL (mean nadir ranged between 67 and 75 mg/dL). Results All 24 intramuscular and 58 of the 59 intranasal doses produced a ≥25 mg/dL rise in glucose from nadir within 20 min of dosing. Times to peak plasma glucose and glucagon levels were similar under both intramuscular and intranasal conditions. Transient nausea occurred in 67% of intramuscular sessions versus 42% of intranasal sessions (P = 0.05); the efficacy and safety of the 2- and 3-mg intranasal doses were similar in the youngest cohorts. Conclusions Results of this phase 1, pharmacokinetic, and pharmacodynamic study support the potential efficacy of a needle-free glucagon nasal powder delivery system for treatment of hypoglycemia in youth with type 1 diabetes. Given the similar frequency and transient nature of adverse effects of the 2- and 3-mg intranasal doses in the two youngest cohorts, a single 3-mg intranasal dose appears to be appropriate for use across the entire 4- to <17-year age range. © 2016 by the American Diabetes Association. Source

Rickels M.R.,University of Pennsylvania | Ruedy K.J.,Jaeb Center for Health Research | Foster N.C.,Jaeb Center for Health Research | Piche C.A.,Locemia Solutions ULC. | And 13 more authors.
Diabetes Care | Year: 2016

Objective Treatment of severe hypoglycemia with loss of consciousness or seizure outside of the hospital setting is presently limited to intramuscular glucagon requiring reconstitution immediately prior to injection, a process prone to error or omission. A needle-free intranasal glucagon preparation was compared with intramuscular glucagon for treatment of insulin-induced hypoglycemia. Research Design and Methods At eight clinical centers, a randomized crossover noninferiority trial was conducted involving 75 adults with type 1 diabetes (mean age, 33±12 years; median diabetes duration, 18 years) to compare intranasal (3 mg) versus intramuscular (1 mg) glucagon for treatment of hypoglycemia induced by intravenous insulin. Success was defined as an increase in plasma glucose to ≥70 mg/dL or ≥20 mg/dL from the glucose nadir within 30 min after receiving glucagon. Results Mean plasma glucose at time of glucagon administrationwas 48±8 and 49±8mg/dL at the intranasal and intramuscular visits, respectively. Success criteria were met at all but one intranasal visit and at all intramuscular visits (98.7% vs. 100%; difference 1.3%, upper end of 1-sided 97.5% CI 4.0%). Mean time to success was 16 min for intranasal and 13 min for intramuscular (P <0.001). Head/facial discomfort was reported during 25% of intranasal and 9% of intramuscular dosing visits; nausea (with or without vomiting) occurred with 35% and 38% of visits, respectively. Conclusions Intranasal glucagon was highly effective in treating insulin-induced hypoglycemia in adults with type 1 diabetes. Although the trial was conducted in a controlled setting, the results are applicable to real-world management of severe hypoglycemia, which occurs owing to excessive therapeutic insulin relative to the impaired or absent endogenous glucagon response. © 2016 by the American Diabetes Association. Source

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