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  • 1
    In: Diabetes Care, American Diabetes Association, Vol. 44, No. 5 ( 2021-05-01), p. 1219-1227
    Abstract: In observational data, lower levels of lipoprotein(a) have been associated with greater prevalence of type 2 diabetes. Whether pharmacologic lowering of lipoprotein(a) influences incident type 2 diabetes is unknown. We determined the relationship of lipoprotein(a) concentration with incident type 2 diabetes and effects of treatment with alirocumab, a PCSK9 inhibitor. RESEARCH DESIGN AND METHODS In the ODYSSEY OUTCOMES trial alirocumab was compared with placebo in patients with acute coronary syndrome. Incident diabetes was determined from laboratory, medication, and adverse event data. RESULTS Among 13,480 patients without diabetes at baseline, 1,324 developed type 2 diabetes over a median 2.7 years. Median baseline lipoprotein(a) was 21.9 mg/dL. With placebo, 10 mg/dL lower baseline lipoprotein(a) was associated with hazard ratio 1.04 (95% CI 1.02−1.06, P & lt; 0.001) for incident type 2 diabetes. Alirocumab reduced lipoprotein(a) by a median 23.2% with greater absolute reductions from higher baseline levels and no overall effect on incident type 2 diabetes (hazard ratio 0.95, 95% CI 0.85–1.05). At low baseline lipoprotein(a) levels, alirocumab tended to reduce incident type 2 diabetes, while at high baseline lipoprotein(a) alirocumab tended to increase incident type 2 diabetes compared with placebo (treatment–baseline lipoprotein(a) interaction P = 0.006). In the alirocumab group, a 10 mg/dL decrease in lipoprotein(a) from baseline was associated with hazard ratio 1.07 (95% CI 1.03−1.12; P = 0.0002) for incident type 2 diabetes. CONCLUSIONS In patients with acute coronary syndrome, baseline lipoprotein(a) concentration associated inversely with incident type 2 diabetes. Alirocumab had neutral overall effect on incident type 2 diabetes. However, treatment-related reductions in lipoprotein(a), more pronounced from high baseline levels, were associated with increased risk of incident type 2 diabetes. Whether these findings pertain to other therapies that reduce lipoprotein(a) is undetermined.
    Type of Medium: Online Resource
    ISSN: 0149-5992 , 1935-5548
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2021
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  • 2
    In: Diabetes Care, American Diabetes Association, Vol. 41, No. 9 ( 2018-09-01), p. 1887-1894
    Abstract: We tested the ability of a type 1 diabetes (T1D) genetic risk score (GRS) to predict progression of islet autoimmunity and T1D in at-risk individuals. RESEARCH DESIGN AND METHODS We studied the 1,244 TrialNet Pathway to Prevention study participants (T1D patients’ relatives without diabetes and with one or more positive autoantibodies) who were genotyped with Illumina ImmunoChip (median [range] age at initial autoantibody determination 11.1 years [1.2–51.8], 48% male, 80.5% non-Hispanic white, median follow-up 5.4 years). Of 291 participants with a single positive autoantibody at screening, 157 converted to multiple autoantibody positivity and 55 developed diabetes. Of 953 participants with multiple positive autoantibodies at screening, 419 developed diabetes. We calculated the T1D GRS from 30 T1D-associated single nucleotide polymorphisms. We used multivariable Cox regression models, time-dependent receiver operating characteristic curves, and area under the curve (AUC) measures to evaluate prognostic utility of T1D GRS, age, sex, Diabetes Prevention Trial–Type 1 (DPT-1) Risk Score, positive autoantibody number or type, HLA DR3/DR4-DQ8 status, and race/ethnicity. We used recursive partitioning analyses to identify cut points in continuous variables. RESULTS Higher T1D GRS significantly increased the rate of progression to T1D adjusting for DPT-1 Risk Score, age, number of positive autoantibodies, sex, and ethnicity (hazard ratio [HR] 1.29 for a 0.05 increase, 95% CI 1.06–1.6; P = 0.011). Progression to T1D was best predicted by a combined model with GRS, number of positive autoantibodies, DPT-1 Risk Score, and age (7-year time-integrated AUC = 0.79, 5-year AUC = 0.73). Higher GRS was significantly associated with increased progression rate from single to multiple positive autoantibodies after adjusting for age, autoantibody type, ethnicity, and sex (HR 2.27 for GRS & gt;0.295, 95% CI 1.47–3.51; P = 0.0002). CONCLUSIONS The T1D GRS independently predicts progression to T1D and improves prediction along T1D stages in autoantibody-positive relatives.
    Type of Medium: Online Resource
    ISSN: 0149-5992 , 1935-5548
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2018
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  • 3
    In: Diabetes Care, American Diabetes Association, Vol. 42, No. 2 ( 2019-02-01), p. 192-199
    Abstract: There are variable reports of risk of concordance for progression to islet autoantibodies and type 1 diabetes in identical twins after one twin is diagnosed. We examined development of positive autoantibodies and type 1 diabetes and the effects of genetic factors and common environment on autoantibody positivity in identical twins, nonidentical twins, and full siblings. RESEARCH DESIGN AND METHODS Subjects from the TrialNet Pathway to Prevention Study (N = 48,026) were screened from 2004 to 2015 for islet autoantibodies (GAD antibody [GADA], insulinoma-associated antigen 2 [IA-2A] , and autoantibodies against insulin [IAA]). Of these subjects, 17,226 (157 identical twins, 283 nonidentical twins, and 16,786 full siblings) were followed for autoantibody positivity or type 1 diabetes for a median of 2.1 years. RESULTS At screening, identical twins were more likely to have positive GADA, IA-2A, and IAA than nonidentical twins or full siblings (all P & lt; 0.0001). Younger age, male sex, and genetic factors were significant factors for expression of IA-2A, IAA, one or more positive autoantibodies, and two or more positive autoantibodies (all P ≤ 0.03). Initially autoantibody-positive identical twins had a 69% risk of diabetes by 3 years compared with 1.5% for initially autoantibody-negative identical twins. In nonidentical twins, type 1 diabetes risk by 3 years was 72% for initially multiple autoantibody–positive, 13% for single autoantibody–positive, and 0% for initially autoantibody-negative nonidentical twins. Full siblings had a 3-year type 1 diabetes risk of 47% for multiple autoantibody–positive, 12% for single autoantibody–positive, and 0.5% for initially autoantibody-negative subjects. CONCLUSIONS Risk of type 1 diabetes at 3 years is high for initially multiple and single autoantibody–positive identical twins and multiple autoantibody–positive nonidentical twins. Genetic predisposition, age, and male sex are significant risk factors for development of positive autoantibodies in twins.
    Type of Medium: Online Resource
    ISSN: 0149-5992 , 1935-5548
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2019
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  • 4
    Online Resource
    Online Resource
    American Diabetes Association ; 1989
    In:  Diabetes Vol. 38, No. 2 ( 1989-02-01), p. 219-224
    In: Diabetes, American Diabetes Association, Vol. 38, No. 2 ( 1989-02-01), p. 219-224
    Abstract: Cholesterol synthesis is increased two- to threefold in the small intestine of diabetic rats. We have observed, in three separate experiments, that the characteristic increase in small intestinal cholesterol synthesis (SICS) in diabetic rats was prevented by total gastrectomy. Food intake was increased twofold, and the small intestine hypertrophied in the gastrectomized diabetic animals. In normal animals, total gastrectomy resulted in only a very small increase in intestinal cholesterol synthesis. In hyperphagic lactating animals, total gastrectomy did not prevent the characteristic increase in SICS that is usually observed in this hyperphagic model. These results indicatethat the effects of total gastrectomy on preventing an increase in SICS are relatively specific for the diabetic state. The mechanism by which total gastrectomy prevents the increase in intestinalcholesterol synthesis in diabetic animals is unknown. Vagotomy did not prevent the typical increase in intestinal synthesis in diabetic animals. Additionally, selectively removing either the antrum or fundus of the stomach did not prevent the increase in SICS in diabetic animals, indicating that the inhibition requires the removal of the entire stomach. It can be speculated that the stomach produces a substance that induces the increase in SICS observed in diabetic animals and that total gastrectomy removes this stimulatory substance.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 1989
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  • 5
    In: Diabetes Care, American Diabetes Association, Vol. 18, No. 1 ( 1995-01-01), p. 70-76
    Abstract: To evaluate the roles of 1) abdominal radiography, 2) a pressure diagnostic procedure (PDP) using a standardized diluent infusion into the catheter sideport, and 3) radiocontrast imaging of the catheter lumen as procedures for diagnosing catheter malfunction in diabetic patients implanted with a programmable intraperitoneal infusion device. RESEARCH DESIGN AND METHODS Sixteen type I diabetic patients implanted with Infusaid programmable intraperitoneal insulin pumps were studied. The ability of the above three procedures to assist diagnosis of catheter malfunction and distinguish between occlusion and catheter breakage was retrospectively analyzed. Glycated hemoglobin was measured to determine the clinical importance of catheter malfunctions and decreases in pump flow due to insulin aggregation in the pump chamber. RESULTS ; Mean glycated hemoglobin levels increased significantly from 8.0 ± 0.3 to 9.0 ± 0.4% (P & lt; 0.05) before and after catheter malfunction, but not during pump flow slowdowns. Mean peak pressure during PDP was 1.96 ± 0.14 psi (P & lt; 0.01 vs. normal) in reversibly occluded catheters and 1.86 ± 0.35 psi (P & lt; 0.05 vs. normal) in broken catheters, compared with 1.32 ± 0.23 psi in normal catheters. Decay times during PDP were & gt;50 s for both reversibly occluded and broken catheters (P & lt; 0.001 vs. normal of 3.6 ± 0.82 s). Abdominal radiographs and sideport injections of contrast material were used to distinguish the types of broken catheters. CONCLUSIONS Catheter breakage and occlusion are complications in im-plantable insulin infusion systems and result in metabolic deterioration. The presence of a sideport allows pressure data and radiographie procedures to assist in determining the cause of catheter malfunction. A diagnostic algorithm was generated to improve efficiency in investigating catheter problems.
    Type of Medium: Online Resource
    ISSN: 0149-5992 , 1935-5548
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 1995
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  • 6
    Online Resource
    Online Resource
    American Diabetes Association ; 1987
    In:  Diabetes Vol. 36, No. 12 ( 1987-12-01), p. 1365-1371
    In: Diabetes, American Diabetes Association, Vol. 36, No. 12 ( 1987-12-01), p. 1365-1371
    Abstract: Insulin secretion and clearance in response to the administration of oral and intravenous glucose was investigated in nine normal men. C-peptide metabolic kinetics were calculated by analysis of individual C-peptide decay curves after the bolus injection of biosynthetic human C-peptide. Glucose was administered to the subjects on three occasions: as a 75-g oral dose, a 75-g i.v. infusion, and an intravenous glucose infusion at a variable rate adjusted to mimic the peripheral glucose levels obtained after the oral glucose load (matching experiment). Glucose, insulin, and C-peptide concentrations were measured for the subsequent 5 h. The glucose level after the oral glucose load (115.9 ± 2.6 mg/dl, mean ± SE) closely approximated that after the matching experiment (120.5 ± 2.5 mg/dl) but was significantly lower than after 75 g i.v. glucose (127.7 ± 3.4 mg/dl, P & lt; .05). Analysis of the areas under the peripheral concentration curves (60-360 min) showed that the responses of both insulin (52.7 ± 5.6 and 46.5 ± 4.5 pmol · ml−1 300 min1) and C-peptide (252.7 ± 27.5 and 267.0 ± 21.6 pmol · ml−1 · 300 min1) were not significantly different after the oral and 75-g i.v. glucose studies, respectively, whereas in the matching experiment, both the insulin (26.1 ± 3.9 pmol · ml−1 · 300 min−1) and C-peptide (178.0 ± 18.9 pmol ml−1 300 min−1) responses were lower (P & lt; .05) than in the other two studies. Insulin secretory rates were derived from peripheral C-peptide concentrations with an open two-compartment model and individually derived model parameters. The basal insulin secretion rate was 86.8 ± 2.9 pmol/min. The insulin secretory response over the 300 min was 66.2 ± 4.8 nmol after oral glucose. This was similar to that after 75 g i.v. glucose (72.4 ± 4 . 1 nmol), whereas that secreted in response to the matching experiment was lower (47.6 ± 4.1 nmol, P ± .05). As a measure of the clearance of endogenous insulin, the ratio between the area under the insulin secretory curve and the area under the peripheral insulin concentration curve was calculated. This ratio was similar (1906 ± 149 ml/min) during the baseline period and the matching glucose infusion (2042 ± 245 ml/min) but was significantly lower after oral glucose (1330 ±112 ml/min, P & lt; .05). The incretin effect calculated based on the insulin secretion rate (25 ± 9.2%) appeared to be less than if the calculations were based on peripheral insulin levels. These data demonstrate that equivalent doses of glucose administered orally and intravenously elicit an equivalent insulin secretory response. However, when the arterialized plasma glucose curve after 75 g oral glucose is matched by an intravenous glucose infusion, only 35.6 ± 2.9 g glucose was infused, and the intravenous glucose resulted in a lower secretory response. Furthermore, after oral administration of 75 g glucose a significant reduction in insulin clearance resulted. These data provide evidence that the hyperinsulinemia seen after oral glucose is due both to enhanced insulin secretion and diminished insulin clearance.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 1987
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  • 7
    Online Resource
    Online Resource
    American Diabetes Association ; 1981
    In:  Diabetes Vol. 30, No. 3 ( 1981-03-01), p. 219-225
    In: Diabetes, American Diabetes Association, Vol. 30, No. 3 ( 1981-03-01), p. 219-225
    Abstract: Recent studies indicate a link between carbohydrate intake and the functional state of the sympathetic nervous system. Fasting or carbohydrate restriction decreases sympathetic activity, while glucose ingestion or dietary supplementation with sucrose increases sympathetic nerve activity. To examine the potential contributions of hyperglycemia and hyperinsulinemia to sympathetic stimulation, sympathetic activity was assessed by measurement of plasma norepinephrine (NE) levels and concomitant cardiovascular indices in nonobese young men during glucose and insulin infusions using glucose clamp techniques. In the insulin infusion studies (euglycemic glucose clamp), insulin was administered at 2 mU/kg/min and 5 mU/kg/min for 2 h while blood glucose was maintained at basal levels by a variable rate of glucose infusion. In the hyperglycemic studies, blood glucose was raised 125 mg/dl above basal and maintained at that level for 2h. In response to both insulin infusions, plasma NE rose progressively over the course of the study, increasing 50% with the 2-mU infusion (from mean basal value of 240 ± 34 pg/ml to 360 ± 41 at 150 min, P & lt; 0.001 for changes over time by analysis of variance) and 117% with the 5-mil infusion (from 254 ± 20 pg/ml to 551 ± 88 at 150 min, P & lt; 0.001). The plasma NE response was greater with the 5-mll than with the 2-mU insulin infusion (P & lt; 0.001), and similarly, was greater during the 2-mU insulin infusion than during a control test in which neither insulin nor glucose was infused (P & lt; 0.001). Associated with the elevations in plasma NE In the 2-mU insulin infusion were increases in pulse rate (P & lt; 0.05), pulse pressure (P & lt; 0.005), and pulse rate - systolic blood pressure product (P & lt; 0.01), and during the 5-mU insulin infusions there were increases in pulse pressure (P & lt; 0.001), mean arterial blood pressure (P & lt; 0.001), and pulse rate - systolic blood pressure product (P & lt; 0.001). Plasma NE did not change during the hyperglycemic glucose clamp nor during control tests, and pulse pressure in the hyperglycemic studies (P & lt; 0.005) was the only cardiovascular measurement increased by these two infusion protocols. The clearance of NE in three subjects was unaffected by the 2-mU insulin infusion. Thus, insulin infusion increases sympathetic nervous system activity in the absence of changes in blood glucose.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 1981
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  • 8
    Online Resource
    Online Resource
    American Diabetes Association ; 1988
    In:  Diabetes Vol. 37, No. 9 ( 1988-09-01), p. 1195-1201
    In: Diabetes, American Diabetes Association, Vol. 37, No. 9 ( 1988-09-01), p. 1195-1201
    Abstract: Urine C-peptide (UCP) has been proposed as a measure of insulin secretion, because insulin and C-peptide are cosecreted in equimolar concentrations by the pancreatic β-cell. The validity of this approach was tested by comparing insulin secretion rates, calculated by application of a two-compartmental analysis of peripheral C-peptide concentrations, with UCP excretion rates. Insulin secretion and UCP excretion with subjects on a mixed diet were simultaneously measured over a 24-h period in 13 patients with non-insulin-dependent diabetes mellitus and in 14 matched nondiabetic control subjects. The fraction of secreted C-peptide that was excreted in the urine (fractional C-peptide excretion) showed considerable intersubject variability in the diabetic (11.3 ± 1.6%, range 3.9–20.8) and control (8.0 ± 1.7%, range 1.1–27.9, P = .07) subjects (means ± SE). UCP clearance demonstrated a similar degree of variability and was not significantly different (P = .07) between diabetic (23.8 ± 3.0 ml/min) and control (16.5 ± 2.7 ml/min) subjects. In control subjects, the 24-h insulin secretion rate correlated more closely with the fasting insulin secretion rate (r = .97, P = .0001), fasting C-peptide (r = .81, P = .0005), and fasting insulin (r = .80, P = .0005) concentrations than with the 24-h UCP excretion rate (r = .62, P = .02). Similar results were obtained in the diabetic patients. The mean coefficient of variation of fractional UCP excretion in 7 nondiabetic control subjects who were studied on a mixed diet over a 24-h period on two occasions was 28.4 ± 10.5%, that of UCP clearance was 28.9 ± 8.6%, and that of simultaneously measured creatinine clearance was 7.8 ± 3.5%. In summary, the fraction of secreted C-peptide that appears in the urine varies considerably between subjects and in the same subject studied repeatedly. UCP excretion does not correlate as well with 24-h insulin secretion as does the fasting insulin secretion rate or the fasting C-peptide or fasting insulin concentration. We conclude that, because the fraction of secreted C-peptide that is excreted in the urine varies considerably between subjects and in the same subject studied on different occasions, UCP is of only limited value as a quantitative measure of endogenous insulin secretion.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 1988
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  • 9
    In: Diabetes Care, American Diabetes Association, Vol. 14, No. 7 ( 1991-07-01), p. 544-547
    Abstract: To identify the circulating species of insulin after separation by high-performance liquid chromatography (HPLC) in patients with factitious hypoglycemia. Research Design and Methods In three of four patients presented, the diagnosis of surreptitious insulin injection was made by documenting the presence of animal insulin in the circulation after separation of the circulating insulin forms by HPLC. Results Animal insulin was identified. Conclusions Thus, the identification of the circulating form of insulin in the circulation by HPLC may be a useful adjunct in the diagnosis of factitious hypoglycemia if animal insulin has been injected and if the simultaneously measured concentrations of insulin and C-peptide are inconclusive.
    Type of Medium: Online Resource
    ISSN: 0149-5992 , 1935-5548
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 1991
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  • 10
    Online Resource
    Online Resource
    American Diabetes Association ; 1987
    In:  Diabetes Vol. 36, No. 11 ( 1987-11-01), p. 1223-1229
    In: Diabetes, American Diabetes Association, Vol. 36, No. 11 ( 1987-11-01), p. 1223-1229
    Abstract: Studies by our and other laboratories have demonstrated that cholesterol synthesis is increased in the small intestine of insulinopenic diabetic animals. In normal animals, many factors have been shown to regulate cholesterol synthesis in the small intestine, including changes in plasma cholesterol levels. The purpose of this study was to determine the effect of lowering plasma cholesterol levels on small intestine cholesterol synthesis in streptozocin-induced diabetic rats. In diabetic rats, 4-aminopyrazolo[3,4-d]pyrimidine (4-APP)-induced hypocholesterolemia (plasma cholesterol levels 20 mg/dl) resulted in a 2.5-fold increase in small intestine cholesterol synthesis, which was most marked in the distal small intestine, decreasing proximally. In the distal small intestine the incorporation of 3H2O into cholesterol was 0.28 ± 0.04 μmol · h−1 · g−1 in diabetic rats versus 1.60 ± 0.38 in diabetic rats administered 4-APP (P & lt; .01). This stimulation of cholesterol synthesis occurred in the upper villus, middle villus, and crypt cells isolated from the middle intestine of the 4-APP-treated diabetic animals. In agreement with these observations, “functional hypocholesterolemia” due to Triton WR-1339 administration also stimulated cholesterol synthesis 2.5-fold in the small intestine of normal and diabetic animals. In the distal small intestine, cholesterol synthesis was 0.43 ± 0.10 μmol · h−1 · g−1 in the diabetic rats versus 1.08 ± 0.21 in diabetic rats treated with Triton WR-1339 (P & lt; .05). In both the 4-APP and Triton WR-1339 experiments, the response of the diabetic rats was similar to that observed in normal rats. Moreover, cholesterol administered orally could prevent the Triton WR-1339-induced increase in small intestine cholesterol synthesis, indicating that providing cholesterol via an alternate route (i.e., intraluminal) can block the increase in synthesis. The results reported in this article, together with our earlier observations demonstrating that luminal factors regulate cholesterol synthesis, indicate that small intestine cholesterol synthesis in diabetic animals is regulated by both luminal and circulating factors in the expected fashion.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 1987
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