bluuebunny/crossref_metadata_2025 huggingface dataset:
Plasma Endothelin-1 Levels in Obese Hypertensive and Normotensive Men
Authors: Ferri Claudio , Bellini Cesare , Desideri Giovambattista , Di Francesco Letizia , Baldoncini Roberta , Santucci Anna , De Mattia Giancarlo
Published: September 2013

Plasma endothelin-1 (ET-1) levels were studied in 15 obese hypertensive (mean age 48.5 ± 3.9 years) and 15 obese normotensive men (mean age 49.5 ± 3.6 years) before and after weight loss due to an 800 kcal/day diet lasting 12 weeks. Circulating peptide concentrations were also assessed in nonobese hypertensive (n = 11) and normotensive men (n = 12). Baseline plasma ET-1 levels were similar in obese hypertensive (0.87 ± 0.22 pg/ml) and obese normotensive men (0.91 ± 0.30 pg/ml). In seven obese hypertensive men, caloric restriction normalized blood pressure levels (systolic: from 166.6 ± 8.1 to 145.0 ± 6.3 mmHg, P < 0.0001; diastolic: from 106.6 ± 5.1 to 89.1 ± 2.0 mmHg, P < 0.0001) and decreased body mass index (BMI) (from 33.4 ± 1.6 to 29.6 ± 2.1 kg/m2, P < 0.002) and plasma ET-1 levels (from 0.93 ± 0.21 to 0.64 ± 0.26 pg/ml, P < 0.05). In the remaining obese hypertensive men (n = 8), blood pressure levels were not normalized by caloric restriction despite a significant decrease of BMI and plasma ET-1 levels (from 0.83 ± 0.23 to 0.60 ± 0.16 pg/ml, P < 0.04). Weight loss also significantly decreased BMI and ET-1 (from 0.91 ± 0.30 to 0.65 ± 0.19 pg/ml, P < 0.01) in obese normotensive men. Baseline ET-1 and fasting insulin levels were significantly correlated in obese hypertensive (r = 0.518, P < 0.05) and obese normotensive men (r = 0.535, P < 0.04). Changes in fasting insulin levels correlated with corresponding changes in plasma ET-1 levels after weight loss in both obese hypertensive (r = 0.558, P < 0.04) and obese normotensive men (r = 0.596, P < 0.02). Moreover, plasma peptide levels were significantly higher (P < 0.02) in obese hypertensive and obese normotensive men than in nonobese normotensive men (0.58 ± 0.28 pg/ml). In conclusion, this study shows that plasma ET-1 concentrations are increased in human obesity. The increase could depend on fasting insulin concentrations, abnormal peptide clearance, or both. Hypertension does not influence the behavior of plasma ET-1 levels in obese men.
Effects of Recent, Short-Term Hyperglycemia on Responses to Hypoglycemia in Humans: Relevance to the Pathogenesis of Hypoglycemia Unawareness and Hyperglycemia-Induced Insulin Resistance
Authors: Fanelli Carmine , Pampanelli Simone , Calderone Stella , Lepore Mauro , Annibale Bruno , Compagnucci Pietro , Brunetti Paolo , Bolli Geremia B
Published: September 2013

A single episode of recent hypoglycemia increases, whereas long-term hyperglycemia decreases, the glycemic thresholds of responses of counterregulatory hormone and symptoms to subsequent hypoglycemia in humans. To assess whether short-term, antecedent hyperglycemia exerts effects opposite to those observed after acute hypoglycemia, seven normal, nondiabetic subjects and eight insulin-dependent diabetes mellitus (IDDM) patients were studied during hyperinsulinemic-hypoglycemic clamp (sequential, 90-min plateaus of plasma glucose [PG] of 4.3, 3.7, 3.0, and 2.4 mmol/l). Nondiabetic subjects were studied the morning after either 6-h clamped hyperglycemia (PG ∼ 13.5 mmol/l) or euglycemia (PG ∼5 mmol/l) between 1600 and 2200 the previous day (glucose and insulin infused on both occasions), as well as after nocturnal hyperglycemia (PG ∼ 13.5 mmol/l) or euglycemia between 2300 and 0500. The IDDM patients were studied after 15 h of euglycemia or hyperglycemia (∼ 17 mmol/l) but identical hyperinsulinemia (∼ 225 pmol/l) between 1600 and 0700. Neither PG thresholds of counterregulatory hormone, symptoms, onset of cognitive dysfunction to hypoglycemia, nor maximal responses were affected by antecedent, short-term hyperglycemia in normal nondiabetic subjects and IDDM patients (NS). However, the rate of glucose infusion required to maintain hypoglycemic plateaus during hypoglycemia was lower after hyperglycemia (nondiabetic subjects 31.2 ± 3.4 vs. 36.7 ± 4 ³mol · kg−1·min−1, IDDM patients 33 ± 3.1 vs. 42.5 ± 3.9 ³mol · kg−1 · min−1; P < 0.05) indicating greater insulin resistance induced by antecedent hyperglycemia. In conclusion, in contrast to acute hypoglycemia and long-term hyperglycemia, recent, short-term hyperglycemia does not affect physiological responses to hypoglycemia. However, recent, short-term hyperglycemia induces insulin resistance that contributes to glucose counterregulation. This is relevant to IDDM patients who have deficient glucagon and adrenaline responses to hypoglycemia.
Endothelial Dysfunction Precedes Development of Microalbuminuria in IDDM
Authors: Stehouwer Coen D A , Andreas Fischer H R , Van Kuijk Arno W R , Polak Bettine C P , Donker Ab J M
Published: September 2013

In patients with insulin-dependent diabetes mellitus (IDDM), microalbuminuria is a predictor of widespread severe microangiopathy and macroangiopathy. Patients with microalbuminuria show generalized dysfunction of the vascular endothelium, but it is unknown whether endothelial dysfunction precedes the development of microalbuminuria. We examined a cohort of 17 IDDM patients at baseline and on three occasions during a follow-up of (median) 64 months (range 51–89). All had normal (< 15 μg/min) urinary albumin excretion (UAE) at the first three examinations. At the fourth examination, 11 patients had normal UAE and 6 had microalbuminuria (median 25.7 μg/min [range 15.3–42.8]). Compared with patients with normal UAE, microalbuminuric patients had significantly higher plasma levels of von Willebrand factor (vWF), a marker of endothelial dysfunction, at the second (200% [168–274] vs. 131% [69–186]), third (208% [188–270] vs. 125% [82–190]), and fourth examinations (231% [202–269] vs. 132% [88–208], P < 0.0001), but not at baseline (128% [98–161] vs. 122% [87–210]). An increase in vWF preceded the occurrence of microalbuminuria by ∼3 years. The groups did not differ with regard to age, diabetes duration, blood pressure, mean glycated hemoglobin and cholesterol, smoking habits, or extent of retinopathy. Endothelial dysfunction, as estimated by plasma vWF concentration, precedes and may predict the development of microalbuminuria in IDDM.
Role of the Sympathoadrenal System in Exercise-Induced Inhibition of Insulin Secretion: Effects of Islet Transplantation
Authors: Houwing Harmina , Fränkel Kim M A , Strubbe Jan H , Van Suylichem Paul T R , Steffens Anton B
Published: September 2013

The present study was designed to investigate the mechanism leading to inhibition of insulin release during exercise. To investigate the influence of circulating epinephrine and norepinephrine, these catecholamines were infused intravenously in resting islet-transplanted and control rats. The role of neural influences on insulin release was investigated by a swimming exercise study in islet-transplanted and control rats, before and after adrenodemedullation. Streptozotocin-induced diabetic Albino Oxford rats received 5 μl islet tissue into the portal vein, resulting in return of normal basal glucose and insulin levels. Transplanted and control animals were provided with two permanent heart catheters to sample blood and to give infusions. Infusion of epinephrine and norepinephrine did not result in inhibition of plasma insulin levels. Blood glucose levels, as well as nonesterified fatty acids and insulin levels in plasma, were similar in both groups. After the infusion study, the animals were subjected to strenuous swimming. During exercise, plasma insulin levels decreased not only in controls, but also in the islet-transplanted group. Blood glucose and plasma catecholamine responses were identical in both groups. After adrenodemedullation, epinephrine was not detectable and the exercise-induced decrease of insulin was not affected. These results indicate that circulating epinephrine and norepinephrine in physiological concentrations do not cause inhibition of insulin secretion. Since the exercise-induced inhibition of insulin secretion is still present in rats with islet grafts, it seems reasonable to suggest that sympathetic neural influences are responsible for the inhibition of insulin release during exercise and that transplanted islets are sympathetically reinnervated.
No Evidence for Mutations in a Putative β-Cell ATP-Sensitive K+ Channel Subunit in MODY, NIDDM, or GDM
Authors: Zhang Yun , Warren-Perry Margaret , Sakura Hiroshi , Adelman John , Stoffel Markus , Bell Graeme I , Ashcroft Frances M , Turner Robert C
Published: September 2013

The β-cell ATP-sensitive K+ (K-ATP) channel has a major role in glucose-induced insulin secretion. Screening the entire coding sequence of the gene for a putative β-cell K-ATP channel subunit, K-ATP2, with single-strand conformation polymorphism did not show any mutations associated with diabetes in white Caucasian diabetic patients, including five pedigrees with maturity onset diabetes of the young (MODY), 25 patients with noninsulin-dependent diabetes mellitus (NIDDM) selected for marked β-cell deficiency, 25 selected for mild diabetes presenting before age 50 years with fasting plasma glucose levels < 10 mmol/l, 25 unselected NIDDM patients, and 25 subjects with gestational diabetes mellitus (GDM) and subsequent raised fasting plasma glucose. In five large MODY pedigrees, linkage analysis with simple tandem-repeat polymorphisms (STRPs) near the K-ATP2 gene excluded linkage. In a population association study, no linkage disequilibrium for the STRP was found between 237 unselected white Caucasian NIDDM patients and 104 geographically matched and age-matched white Caucasian nondiabetic subjects. In addition, two silent polymorphisms were found with similar frequency in nondiabetic and diabetic subjects. Mutations in the gene for K-ATP2 are unlikely to be a major cause of MODY, NIDDM, or GDM.
HLA-DQB1*0602 Is Associated With Dominant Protection From Diabetes Even Among Islet Cell Antibody–Positive First-Degree Relatives of Patients with IDDM
Authors: Pugliese Alberto , Gianani Roberto , Moromisato Rocio , Awdeh Zuheir L , Alper Chester A , Erlich Henry A , Jackson Richard A , Eisenbarth George S
Published: September 2013

HLA-DQB1 alleles confer susceptibility and resistance to insulin-dependent diabetes mellitus (IDDM). We investigated whether the susceptibility alleles DQB1*0302 and DQB1*0201 affect progression to diabetes among islet cell antibody–positive (ICA+) first-degree relatives of IDDM patients and whether the protective allele DQB1*0602 can be found and is still protective among such relatives. We human leukocyte antigen–typed and periodically tested β-cell function (first-phase insulin release [FPIR] during the intravenous glucose tolerance test) in 72 ICA+ relatives, of whom 30 became diabetic on follow-up (longest follow-up 12 years); 54 (75%) relatives carried DQB1*0302 and/or DQB1*0201. The frequency of DQB1*0302 and DQB1*0201 and of the high-risk genotype DQB1*0302/DQB1*0201 did not differ significantly between diabetic relatives and those remaining nondiabetic. On follow-up, progression to IDDM was not statistically different for relatives with or without the DQB1*0302/DQB1*0201 genotype. However, those relatives with the DQB1*0302/DQB1*0201 genotype had a tendency to develop diabetes at an earlier age (log-rank P = 0.02). We found DQB1*0602 in 8 of 72 (11.1%) ICA+ relatives. Relatives with DQB1*0602 did not develop diabetes or show any decline of FPIR versus 28 of 64 DQB1*0602– relatives who developed IDDM (log-rank P = 0.006; Wilcoxon's P = 0.02). The protective allele DQB1*0602 is found in ICA+ relatives who have minimal risk of progression to IDDM. Therefore, DQB1*0602 is associated with protection from IDDM both in population studies and among relatives with evidence of autoimmunity who should not enter prevention trials.
Glucagon-Like Peptide I Reduces Postprandial Glycemic Excursions in IDDM
Authors: Dupre John , Behme Margaret T , Hramiak Irene M , McFarlane Philip , Williamson M Paul , Zabel Pamela , McDonald Thomas J
Published: September 2013

Effects of human glucagon-like peptide I (GLP-I)(7–36)amide were examined in volunteers having insulin-dependent diabetes mellitus (IDDM) with residual C-peptide (CP) secretion (n = 8, 7 men and 1 woman; age, 31 ± 1.4 years; body mass index, 24.7 ± 0.7 kg/m2; duration of diabetes, 3.2 ± 0.8 years; insulin dose, 0.41 ± 0.05 U · kg−1· day−1; meal-stimulated CP, 1.0 ± 0.2 nmol/l [means ± SE]). After a mixed meal (Sustacal, 30 kJ/kg body wt), intravenous injection of GLP-I, 1.2 pmol · kg−1 · min−1 through 120 min, virtually abolished increments of plasma glucose, CP, pancreatic polypeptide (PP), and glucagon concentrations, with no significant effect on plasma gastrin levels during the infusions. At reduced dosage (0.75 pmol · kg−1 · min−1), GLP-I had lesser effects on plasma glucose and CP levels. On cessation of intravenous GLP-I infusions after the meals, plasma glucose, CP, PP, and glucagon concentrations rebounded toward control levels by 180 min, and the response of plasma gastrin was prolonged. These rebound responses are consistent with intestinal delivery of food retained in the stomach on escape from inhibition of gastric emptying by GLP-I. Infusion of 1.2 pmol · kg−1 · min−1 GLP-I with 20 g glucose (10% dextrose in water) injected intravenously over 60 min enhanced plasma responses of immunoreactive CP; the mean incremental areas under concentration curves (0–60 min) increased sixfold, but the glycemic excursion was not affected. Thus, in CP-positive IDDM, pharmacological doses of GLP-I reduce glycemic excursions after meals by a mechanism(s) not dependent on stimulation of insulin secretion, presumably involving delayed gastric emptying. This effect of the peptide on blood glucose levels after meals may have therapeutic implications in both IDDM and non-insulin-dependent diabetes.
Disease Sensitivity and Specificity of 52 Assays for Glutamic Acid Decarboxylase Antibodies: The Second International GADAB Workshop
Authors: Schmidli Robert S , Colman Peter G , Bonifacio Ezio
Published: September 2013

There is increasing interest in the use of glutamic acid decarboxylase antibodies (GADAbs) for identification of subjects at increased risk of developing insulin-dependent diabetes mellitus (IDDM). However, considerable variation exists between laboratories in the reported frequency of GADAb in various clinical situations, and disease sensitivity and specificity have not yet been compared between assays. An international workshop was held in which 101 coded freeze-dried sera, including 39 from subjects with newly diagnosed IDDM, 32 from healthy control subjects, 4 from nondiabetic subjects with Graves' disease, and 4 from islet cell antibody–positive subjects, were analyzed in 52 assays (radiobinding assay [RBA], 26; enzyme-linked immunosorbent assay [ELISA], 19; and enzymatic immunoprecipitation assay [EIP], 7). The mean sensitivity for RBAs (76.2%) was higher than for ELISAs (36.5%) and EIPs (49.9%) (P < 0.01). The mean specificity was similar for each assay format (RBA, 89.4%; ELISA. 89.4%; and EIP, 92.3%). The lower sensitivities of the ELISA and EIP were predominantly due to the inability of these assays to detect low levels of GADAb in IDDM. To convert results to standard units, standard curves were constructed using duplicate dilutions of the anti–glutamic acid decarboxylase monoclonal antibody MICA 3 and serum from a patient with stiff-man syndrome (SMS). Curves could be derived in 28 assays using the MICA 3 serum and in 29 using the SMS serum. The mean coefficients of variation between assays for disease and control samples were 45% when results were converted to MICA units, 77% for SMS units, and 76% for SD scores. The relatively lower scatter observed using the MICA 3 serum as a standard indicates that this serum may be useful as an international reference. Because assays for GADAb with a high level of sensitivity and specificity are now available, prospective studies are now required to establish the role of GADAbin clinical applications such as preclinical screening for IDDM.
Insulin-Induced Sympathetic Activation and Vasodilation in Skeletal Muscle: Effects of Insulin Resistance in Lean Subjects
Authors: Vollenweider Laurent , Tappy Luc , Owlya Reza , Jéquier Eric , Nicod Pascal , Scherrer Urs
Published: September 2013

Insulin-induced stimulation of blood flow and sympathetic nerve activity in skeletal muscle tissue is impaired in obesity, but the underlying mechanism is unknown. To determine whether insulin resistance alters sympathetic and vasodilatory responses to euglycemic hyperinsulinemia, in eight healthy subjects we measured calf blood flow and muscle sympathetic nerve activity (MSNA) (n = 5) during insulin/glucose infusion (euglycemic hyperinsulinemic [6 pmol · kg−1 · min−1] clamp) performed alone and performed during concomitant fat emulsion infusion, a maneuver designed to induce insulin resistance. The major new finding is that fat emulsion infusion, which attenuated insulin-induced stimulation of carbohydrate oxidation by 39 ± 7% (P < 0.01), did not have any detectable effect on insulin-induced vasodilatory and sympathetic responses: at the end of the 2-h clamp, blood flow and MSNA had increased by 35 ± 6% (P < 0.01) and 152 ± 58% (P < 0.01), respectively, during insulin infusion alone and by 35 ± 7% (P < 0.01) and 244 ± 90% (P < 0.01), respectively, during insulin infusion superimposed on free fatty acid infusion. These observations in lean healthy subjects indicate that induction of resistance to the stimulatory effects of insulin on carbohydrate metabolism does not attenuate muscle blood flow and MSNA responses evoked by acute euglycemic hyperinsulinemia. These findings provide further evidence that hyperinsulinemia per se is the primary stimulus that triggers stimulation of muscle blood flow and MSNA during insulin/glucose infusion in humans and suggest that the impaired insulin-induced vasodilation in obese subjects is not related primarily to impaired stimulation of muscle carbohydrate metabolism.
Effects of Angiotensin-Converting Enzyme Inhibitors, Ca2+ Channel Antagonists, and α-Adrenergic Blockers on Glucose and Lipid Metabolism in NIDDM Patients With Hypertension
Authors: Giordano Mauro , Matsuda Masafumi , Sanders Leonard , Canessa Mitzy L , DeFronzo Ralph A
Published: September 2013

We compared the effects of captopril, nifedipine, and doxazosin on glucose and lipid metabolism in 30 hypertensive non-insulin-dependent diabetes mellitus (NIDDM) patients (age = 50 ± 3 years; body mass index = 30 ± 1 kg/m2). Of these patients, 9 were treated with captopril, 11 with nifedipine, and 10 with doxazosin for 12 weeks. Blood pressure, fasting plasma glucose (FPG) concentration, HbA1c, oral glucose tolerance test (OGTT), euglycemic insulin clamp, and plasma lipids were measured before and after a 3-month period. Mean arterial blood pressure (114 ± 2 mmHg) was similar in all groups before initiating antihypertensive therapy and declined to 102 ± 2 (captopril), 103 ± 1 (nifedipine), and 103 ± 2 (doxazosin) mmHg (P < 0.001). Baseline FPG (148 ± 11 mg/dl) and HbA1c (6.3 ± 1%) were similar in all groups and did not change significantly with treatment. Plasma glucose, insulin, and free fatty acid (FFA) concentrations during the OGTT were similar in all groups before antihypertensive treatment and did not change with captopril and nifedipine; after doxazosin, plasma glucose and FFA concentrations during the OGTT decreased (both P < 0.05) without change in plasma insulin response. Insulin-mediated glucose uptake (144 ± 11 mg · m−2 · min−1), glucose oxidation (76 ± 4 mg · m−2 · min−1), and nonoxidative glucose disposal (71 ± 6 mg · m−2 · min−1) were similar in all groups before the start of antihypertensive treatment and did not change in captopril and nifedipine groups. After doxazosin, total glucose uptake (180 ± 25 mg · m−1) increased significantly (P < 0.01); nonoxidative glucose disposal did not change. Plasms lipid levels improved after doxazosin therapy; high-density lipoprotein rose from 40 ± 3 to 44 ± 3 mg/dl (P <0.01 and triglycerides fell from 210 ± 18 to 178 ± 17 (P < 0.05). No changes in plasma lipid levels were observed with captopril or nifedipine. We concluded that in hypertensive NIDDM subjects, 1) captopril, nifedipine, and doxazosin are equally effective in lowering blood pressure; 2) captopril and nifedipine have no adverse effects on glucose tolerance, insulin sensitivity, ot plasma lipid profile; and 3) doxazosin significantly improves insulin sensitivity during the euglycemic insulin clamp, enhances OGTT while decreasing the plasma insulin response, and improves the plasma lipid profile.
Effects of an Acute Increase in Epinephrine and Cortisol on Carbohydrate Metabolism During Insulin Deficiency
Authors: Goldstein Richard E , Abumrad Naji N , Lacy D B , Wasserman David H , Cherrington Alan D
Published: September 2013

This study was undertaken to investigate the effects of an acute increase in the plasma epinephrine level, with or without an accompanying increase in the plasma cortisol level, during selective insulin deficiency on glycogenolysis and gluconeogenesis in conscious overnight-fasted dogs. Experiments consisted of an 80-min tracer and dye equilibration period, a 40-min basal period, and a 180-min experimental period. In all protocols, selective insulin deficiency was created during the experimental period by infusing somatostatin peripherally (0.8 μg · kg−1 · min−1) with basal replacement of glucagon intraportally (0.65 ng · kg−1 · min−1). In EPI+SAL (n = 6), an additional infusion of epinephrine (0.04 μg · kg−1 · min−1) was infused during the experimental period along with saline. In EPI+CORT (n = 6), hydrocortisone (3.0 μg · kg−1 · min−1) was infused in addition to epinephrine during the experimental period. In SAL+CORT (n = 5), hydrocortisone was infused during the experimental period. In SALINE (n = 5), neither epinephrine nor cortisol was infused. [3-3H]glucose, [U-14C]alanine, and indocyanine green dye were used to assess glucose production (rate of appearance [Ra]) and gluconeogenesis using tracer and arteriovenous difference techniques. During selective insulin deficiency in SALINE, the arterial plasma glucose level increased from 6.0 ± 0.1 to 15.8 ± 1.1 mmol/l; Ra increased from 14.7 ± 0.7 to 24.9 ± 1.7 μmol· kg−1 · min−1. Gluconeogenic efficiency and the conversion of alanine and lactate to glucose increased to 300 ± 55 and 355 ± 67% of basal. In EPI+SAL and EPI+CORT, plasma glucose increased from 6.2 ± 0.1 to 19.8 ± 0.9 mmol/l and from 6.3 ± 0.1 to 19.5 ± 0.9 mmol/l. In EPI+SAL and EPI+CORT, Ra increased from 16.5 ± 1.1 to 29.3 ± 3.2 μmol · kg−1 · min−1 and from 15.4 ± 1.3 to 28.3 ± 2.5 μmol.kg−1 · min−1. The rise in gluconeogenic efficiency was similar to the rise that occurred in SALINE, but gluconeogenic conversion increased 17-fold in each of the two epinephrine groups. During the epinephrine infusion, gluconeogenesis accounted for a maximum of 55% of total glucose production as opposed to 31% during insulin deficiency alone. An increase in cortisol alone during insulin deficiency (SAL+CORT) had no effect on glucose level, glucose production, or gluconeogenesis. These results suggest that small increases in the plasma epinephrine level during insulin deficiency can significantly worsen the resulting hyperglycemia through stimulation of both glycogenolysis and gluconeogenesis. The addition of an acute rise in plasma cortisol does not affect glycogenolysis or gluconeogenesis or further worsen the hyperglycemia during insulin deficiency.
Hypoxia Stimulates Glucose Transport in Insulin-Resistant Human Skeletal Muscle
Authors: Azevedo John L , Carey Julie O , Pories Walter J , Morris Patricia G , Dohm G Lynis
Published: September 2013

Insulin and muscle contraction stimulate glucose transport into muscle cells by separate signaling pathways, and hypoxia has been shown to operate via the contraction signaling pathway. To elucidate the mechanism of insulin resistance in human skeletal muscle, strips of rectus abdominis muscle from lean (body mass index [BMI] < 25), obese (BMI > 30), and obese non-insulin-dependent diabetes mellitus (NIDDM) (BMI > 30) patients were incubated under basal and insulin-, hypoxia-, and hypoxia + insulin-stimulated conditions. Insulin significantly stimulated 2-deoxyglucose transport twofold in muscle from lean (P < 0.05) patients, but not in muscle from obese or obese NIDDM patients. Furthermore, maximally insulin-stimulated transport rates in muscle from obese and diabetic patients were significantly lower than rates in muscle from lean patients (P < 0.05). Hypoxia significantly stimulated glucose transport in muscle from lean and obese patients. There were no significant differences in hypoxia-stimulated glucose transport rates among lean, obese, and obese NIDDM groups. Hypoxia + insulin significantly stimulated glucose transport in lean, obese, and diabetic muscle. The results of the present study suggest that the glucose transport effector system is intact in diabetic human muscle when stimulated by hypoxia.
Altered Insulin Secretory Responses to Glucose in Subjects with a Mutation in the MODY1 Gene on Chromosome 20
Authors: Byrne Maria M , Sturis Jeppe , Fajans Stefan S , Ortiz F Javier , Stoltz Anjanette , Stoffel Markus , Smith Marla J , Bell Graeme I , Halter Jeffrey B , Polonsky Kenneth S
Published: September 2013

This study was undertaken to test the hypothesis that the diabetes susceptibility gene on chromosome 20q12 responsible for maturity-onset diabetes of the young (MODY) in a large kindred, the RW family, results in characteristic alterations in the dose-response relationships between plasma glucose concentration and insulin secretion rate (ISR) that differentiate this form of MODY from MODY in subjects with glucokinase mutations. Ten marker-positive subjects and six matched nondiabetic marker-negative subjects from the RW family received graded intravenous glucose infusions on two occasions separated by a 42-h continuous intravenous glucose infusion designed to prime the β-cell to secrete more insulin in response to glucose. ISR was derived by deconvolution of peripheral C-peptide levels. Basal glucose and insulin levels were similar in marker-negative and marker-positive groups (5.3 ± 0.2 vs. 5.0 ± 0.2 mmol/l, P > 0.2, and 86.1 ± 3.9 vs. 63.7 ± 12.1 pmol/l, P > 0.1, respectively). However, the marker-positive subjects had defective insulin secretory responses to an increase in plasma glucose concentrations. Thus, as the glucose concentration was raised above 7 mmol/l, the slope of the curve relating glucose and ISR was significantly blunted in the marker-positive subjects (13 ± 4 vs. 68 ± 8 pmol · min−1 · mmol−1 · 1, P < 0.0001). The reduced insulin secretory responses in the marker-positive subjects were most evident at higher plasma glucose concentrations >7 mmol/1, and differences between the two groups were not significant at lower glucose levels between 5 and 7 mmol/1. After a 42-h glucose infusion, the amount of insulin secreted over the glucose concentration range 5–9 mmol/1 increased by 54 ± 16% in the markernegative subjects. This priming effect of glucose on insulin secretion was not seen in 9 of the 10 markerpositive subjects. In contrast, previous results in MODY subjects with glucokinase mutations showed persistence of the glucose-priming effect on ISR and continued increases, although subnormal, of ISR as plasma glucose concentration rises from 7–12 mmol/1. In conclusion, subjects from the RW family who have inherited the at-risk allele of the MODY1 gene appear to have a characteristic pattern of altered insulin secretory responses to glucose. These alterations are present before the onset of hyperglycemia, suggesting a unique mechanism of (β-cell dysfunction different from the defect in MODY subjects with glucokinase mutations.
The Wisconsin Epidemiologic Study of Diabetic Retinopathy: XVI. The Relationship of C-Peptide to the Incidence and Progression of Diabetic Retinopathy
Authors: Klein Ronald , Klein Barbara E K , Moss Scot E
Published: September 2013

The relationship between plasma C-peptide and the 6-year incidence and progression of diabetic retinopathy was examined in a population-based study in Wisconsin. Individuals with younger-onset (n = 548) and older-onset (n = 459) diabetes were included. C-peptide was measured by radioimmunoassay with Heeling's M1230 antiserum. Retinopathy was determined from stereoscopic fundus photographs. Younger- and older-onset insulinusing individuals with undetectable or low plasma Cpeptide (<0.3 nmol/L) at baseline had the highest incidence and rates of progression of retinopathy, whereas older-onset individuals with C-peptides >0.3 nmol/1 had the lowest incidence and rates of progression of retinopathy. However, within each group (youngeronset using insulin, older-onset using insulin, and olderonset not using insulin), after we controlled for other characteristics associated with retinopathy, there was no relationship between higher levels of C-peptide at baseline and lower 6-year incidence or progression of retinopathy. These data suggest that glycemic control, and not C-peptide, is related to the incidence and progression of diabetic retinopathy.
The Insulin Gene Promoter: A Simplified Nomenclature
Authors: German Michael , Ashcroft Stephen , Docherty Kevin , Edlund Helena , Edlund Thomas , Goodison Steven , Imura Hiroo , Kennedy Giulia , Madsen Ole , Melloul Danielle , Moss Larry , Olson Karl , Permutt M Alan , Philippe Jacques , Robertson R Paul , Rutter William J , Serup Palle , Stein Roland , Steiner Donald , Tsai Ming-Jer , Walker Michael D
Published: September 2013

The tools of molecular biology have rapidly expanded our knowledge of how β-cells regulate insulin gene expression. As this work has progressed in parallel in different laboratories, alternate nomenclature systems have been developed to describe the functionally important elements of the insulin gene. This jumble of names is confusing to those outside the field and intimidating to neophytes. Therefore, we have agreed to a simple, uniform set of names for the major insulin gene promoter elements.
Intrathymic Transplantation of Islet Antigen Affects CD8+ Diabetogenic T-Cells Resulting in Tolerance to Autoimmune IDDM
Authors: Baumann Elizabeth E , Buckingham Frank , Herold Kevan C
Published: September 2013

The acquisition of T-cell tolerance in the thymus is limited to those antigens expressed in the thymus at the time of T-cell development. Normally, islet antigens that are involved in insulin-dependent diabetes mellitus (IDDM) are not present in the thymus, but we have previously shown that transplantation of islets expressing relevant antigens into the thymus at the time of T-cell maturation results in prevention of IDDM in the multidose streptozotocin model of diabetes mellitus (MDSDM). Although both CD4+ and CD8+ T-cells are involved in the pathogenesis of this disease, the cells affected by intrathymic transplantation of islets are unknown. In this study, we have identified which T-cell subsets are affected by intrathymic islet antigens. Streptozotocin (STZ)-treated syngeneic islets were transplanted into the thymuses of C57BL/KsJ mice, and CD4+, CD8+, or both subsets of cells were transiently depleted with monoclonal antibodies (mAbs). After T-cell repopulation, animals that had received intrathymic islets followed by anti-CD8 mAb (P < 0.05) or both anti-CD4 and anti-CD8 mAbs (P < 0.01) but not anti-CD4 mAb alone were resistant to the development of autoimmune diabetes after five low doses of STZ. Insulitis was also reduced in mice receiving intrathymic islets and anti-CD8 (P < 0.025) or both anti-CD4 and anti-CD8 mAbs (P < 0.001). Treatment of islets with STZ before intrathymic transplantation was needed to induce tolerance. When mice that had been rendered tolerant to MDSDM by treatment with intrathymic islets and anti-CD3 or antl-CD4 plus anti-CD8 mAbs received an adoptive transfer of spleen cells from normal donor mice depleted of CD4+ but not CD8+ cells, susceptibility to diabetes was restored and hyperglycemia (P = 0.02) as well as insulitis developed. We conclude that the induction of tolerance after intrathymic transplantation of antigen-bearing islets affects developing CD8+ but not CD4+ diabetogenic T-cells.
Peroxidative Stress in Diabetic Blood Vessels: Reversal by Pancreatic Islet Transplantation
Authors: Pieper Galen M , Jordan Milan , Dondlinger Lynn A , Adams Mark B , Roza Allan M
Published: September 2013

Diabetic complications are believed to arise, in part, through an increase in oxidative stress. We characterized antioxidant status in vascular tissue in untreated diabetic rats and in diabetic rats rendered euglycemic by pancreatic islet transplantation. Three key endogenous antioxidant enzymes (e.g., superoxide dismutase, catalase, and glutathione peroxidase) were measured. Sprague-Dawley rats with streptozotocin-induced diabetes were killed after 8 weeks of untreated hyperglycemia and compared with age-matched controls. Eight weeks of untreated diabetes resulted in a significant increase of tissue catalase in aorta, iliac artery, and femoral artery as compared with controls. No significant changes in either superoxide dismutase or glutathione peroxidase were observed in aorta, iliac artery, or femoral artery of diabetic animals. This increase in catalase in diabetic vascular tissue suggests increased oxidative stress due to chronic exposure to H2O2 in vivo. To assess the impact of islet transplantation on oxidative stress in vascular tissue, inbred Lewis strain rats were rendered diabetic with streptozotocin. After 8 weeks of untreated diabetes, rats received an intraportal islet isograft and were monitored for 4 subsequent weeks of euglycemia. Islet transplantation improved weight gain and normalized blood glucose and total glycosylated hemoglobin. While catalase was significantly increased in aorta and iliac artery at 8 and 12 weeks of diabetes, vascular catalase was restored to normal by islet transplantation. These data suggest that islet transplantation is an effective treatment strategy to minimize increased oxidative stress in diabetic vasculature.
Comparative Study of the Protective Effect Afforded by Intravenous Administration of Bovine or Ovine Insulin to Young NOD Mice
Authors: Hutchings Patricia R , Cooke Anne
Published: September 2013

Soluble bovine or ovine insulin given intravenously to female NOD mice shortly after weaning had a downregulating effect on several autoimmune parameters associated with insulin-dependent diabetes. The titer of spontaneous anti-insulin antibodies was reduced, insulitis was delayed and less severe, and only 25% of treated mice were diabetic at 30 weeks compared with 70% of untreated mice. An interesting paradox occurred in that bovine insulin, although poorly immunogenic in NOD mice and ineffective as a tolerogen for complete Freund's adjuvant–induced cellular and humoral responses to ovine insulin, was nearly as effective as immunogenic ovine insulin in protecting against diabetes and better than ovine insulin at downregulating spontaneous autoantibodies to insulin. Bovine and ovine insulins differ by only one amino acid on the A-chain loop, but whereas modulation of the induced response to ovine insulin appeared to be sheep-specific, modulation of the induced and spontaneous autoimmunity was achieved almost equally well by bovine or ovine insulin. We suggest therefore that modulation of the induced and spontaneous responses are dependent on different T-cell epitopes and that modulation of spontaneous autoimmunity appears to be governed by an epitope common to both insulins.
Ten-Year Incidence of Gross Proteinuria in People With Diabetes
Authors: Klein Ronald , Klein Barbara E K , Moss Scot E , Cruickshanks Karen J
Published: September 2013

There are few population-based epidemiological data describing the long-term incidence of gross proteinuria in people with diabetes. We performed a population-based study in southern Wisconsin of individuals with diabetes diagnosed at either <30 years of age and taking insulin (younger-onset, n = 666) or ≥30 years of age either taking (older-onset taking insulin, n = 376) or not taking insulin (older-onset not taking insulin, n = 418). The presence of gross proteinuria (≥0.3 g/1) was determined by means of a reagent strip. The incidence of proteinuria in the 10-year interval was 28% in the younger-onset group, it was 40% in the older-onset group taking insulin, and it was 33% in the older-onset group not taking insulin. After we controlled for other risk factors, the 10-year incidence of proteinuria was significantly related to higher glycosylated hemoglobin level and diastolic blood pressure at baseline and to an increase in glycosylated hemoglobin level and an increase in diastolic blood pressure from baseline to the 4-year follow-up in the younger-onset group and to higher glycosylated hemoglobin level, higher systolic blood pressure, and higher total pack-years of cigarettes smoked at baseline and an increase in systolic blood pressure from baseline to the 4-year follow-up in the older-onset groups. These data suggest that modification of three factors—hyperglycemia, high blood pressure, and smoking—may lead to a reduction in the long-term incidence of proteinuria.
Identification of Microsatellite Markers Near the Human ob Gene and Linkage Studies in NIDDM-Affected Sib Pairs
Authors: Stirling Brigid , Cox Nancy J , Bell Graeme I , Hanis Craig L , Spielman Richard S , Concannon Patrick
Published: September 2013

Non-insulin-dependent diabetes mellitus (NIDDM) is a complex metabolic disorder with a significant genetic component. Obesity is a frequent complicating factor for NIDDM. In the mouse, a number of single gene defects that result in obesity have been described. Mutations in one of these genes, the ob gene, results in both obesity and NIDDM. Recently, the cloning of the murine ob gene and its human homologue has been reported {Nature 372:425–432, 1994). In the present study, the contribution of genetic variation at the human ob locus to NIDDM susceptibility was assessed by analyzing allele sharing in NIDDM-affected sib pairs (ASPs) for markers located near the human ob gene. Four yeast artificial chromosome clones containing the human ob gene were isolated. These clones colocalized the ob gene and two microsatellite markers, D7S5H and D7S635, to a region of 280 kb on the long arm of human chromosome 7. The microsatellite markers were typed in 346 Mexican-American NIDDM-ASPs derived from 176 families and an additional 110 ethnically and geographically matched controls. No evidence of linkage or association between either microsatellite marker and NIDDM was observed in this population. These results suggest genetic variation in the human ob gene does not play a major role in susceptibility to NIDDM in Mexican-Americans. Diabetes 44:999-1001, 1995
Development of the Implantable Glucose Sensor: What Are the Prospects and Why Is It Taking So Long?
Authors: Gough David A , Armour Jon C
Published: September 2013

The development of an implantable glucose sensor for use in diabetes was first suggested in the 1960s (1–3). The sensor would provide an alternative to the present discrete methods of glucose determination that are based on intermittent blood sampling. Continuous glucose sensing would be particularly important in the detection and management of hypoglycemia. It would also allow early detection of hyperglycemia and provide a basis for insulin administration at more appropriate dosages and timing or for automatic insulin delivery from a pump. An implantable glucose sensor could also be used in parallel with other existing or potential forms of insulin replacement, such as transplantation or hybrid islet devices.
Immunogenetic Determinants and Prediction of IDDM in French Schoolchildren
Authors: Lévy-Marchal Claire , Dubois Frédéric , Noël Michéle , Tichet Jean , Czernichow Paul
Published: September 2013

Islet cell antibodies (ICAs) are predictive markers of the disease in first-degree relatives of patients with insulin-dependent diabetes mellitus (IDDM). The large majority of newly diagnosed cases, however, will develop in children with no family history of diabetes. In France, the risk for development of IDDM up to the age of 20 years is 60 times higher in first-degree relatives than in the general population. The aim of this study was to test whether data collected in the first-degree relatives of IDDM patients could be transferred to children for the prediction of overt diabetes. A large population-based cohort of French school-aged children (n = 13,380; ages 6–17 years) were screened for ICAs, and results were compared with those of 1,185 first-degree relatives of IDDM patients. ICA prevalence rates were significantly different in the two populations (5.5% vs. 1.5%; P < 0.0001), with a significantly higher proportion of high ICA titers in first-degree relatives (37%) than in schoolchildren (14%) (P = 0.0005). ICA titers remained remarkably stable in children over 4 years. Insulin autoantibodies (IAAs) were found in 3.4 and 15.4% of ICA+ children and first-degree relatives, respectively. Susceptibility alleles at the human leukocyte antigen (HLA)-DQB1 locus were observed significantly more frequently in children in whom ICA titers ≥20 Juvenile Diabetes Foundation units (JDF U) were found on two separate occasions (67%) than in ICA− children (52%) (P = 0.05). Five subjects developed overt diabetes during follow-up. ICA titers of > 20 JDF U were found in all of them on the first sample and at follow-up. Four of them were siblings; two of them were also IAA+. One was a child from the group. He was IAA− and had HLA typing of *0201/*0302 at the DQB1 locus. Our results do not strongly support the hypothesis that data derived from family studies can be transferred to the general population for IDDM prediction in children.
Acute Hyperinsulinemia Decreases the Hepatic Secretion of Very-Low-Density Lipoprotein Apolipoprotein B-100 in NIDDM
Authors: Cummings Michael H , Watts Gerald F , Umpleby A Margot , Hennessy Thomas R , Kelly Joanne M , Jackson Nicola C , Sönksen Peter H
Published: September 2013

In a randomized crossover study, we measured the hepatic secretion rate of very-low-density lipoprotein (VLDL) apolipoprotein B-100 (apoB) in seven patients with well-controlled non-insulin-dependent diabetes mellitus (NIDDM) (HbA1 8.4 ± 0.4% [mean ± SE]) on two occasions: during a 13-h hyperinsulinemic (plasma insulin concentration 586 ± 9.7 pmol/l) euglycemic (plasma glucose concentration 5.2 ± 0.1 mmol/l) clamp; and during a 13-h saline (control) infusion. After 5 h of the hyperinsulinemic euglycemic clamp (or saline infusion) when a new steady state of apoB turnover was reached, [1-13C]leucine was administered by a primed (1 mg/kg), constant 8-h infusion (1 mg · kg−1 · h−1). VLDL apoB isotopic enrichment was determined with gas chromatography–mass spectrometry, and a monoexponential model was used to calculate the fractional secretion rate of VLDL apoB. VLDL apoB secretion rate was significantly reduced during the hyperinsulinemic euglycemic clamp compared with the saline study (12.2 ± 3.6 vs. 24.5 ± 7.1 mg · kg−1·day−1, P = 0.001), but there was no change in the fractional catabolic rate of VLDL apoB. Concomitantly, plasma concentrations of nonesterified fatty acids (NEFAs), glycerol, and triglycerides (TGs) were significantly lower during the hyperinsulinemic euglycemic clamp compared with the saline study (NEFAs, P < 0.001; glycerol, P = 0.005; TGs P = 0.004). We conclude that acute hyperinsulinemia decreases the hepatic secretion rate of VLDL apoB in NIDDM, probably in part due to reduction in the delivery of NEFA and glycerol substrate to the liver.
Isolation, Characterization, and Metabolism of the Glycated and Nonglycated Subfractions of Low-Density Lipoproteins Isolated from Type I Diabetic Patients and Nondiabetic Subjects
Authors: Klein Richard L , Laimins Marta , Lopes-Virella Maria F
Published: September 2013

The total low-density lipoprotein (LDL) fraction was isolated from 21 patients with type I diabetes and 7 nondiabetic normolipemic subjects. The LDL was separated into two subfractions, one glycated (G-LDL) and one nonglycated (N-LDL), using affinity chromatography. G-LDL comprised 21.1 ± 3.6 and 5.2 ± 0.6% of the total LDL in diabetic patients and normal subjects, respectively. G-LDL isolated from both diabetic patients and normal subjects was significantly more glycated than N-LDL isolated from the same subject. G-LDL isolated from both diabetic patients and normal subjects was enriched in triglycerides. The metabolism of N-LDL and G-LDL was investigated in human fibroblasts, which express only the classical LDL receptor, and in human monocyte-derived macrophages, which also express a receptor for G-LDL. In fibroblasts, the rates of receptor-mediated accumulation of N-LDL isolated from normal subjects and diabetic patients were significantly greater (P < 0.01) than those of G-LDL. In contrast, when the same LDL subfractions were incubated with human monocyte-derived macrophages, the rates of receptor-mediatedaccumulation of G-LDL isolated from both groups were significantly greater (P < 0.01) than those of N-LDL. Rates of degradation of G-LDL by human macrophages were not significantly different from those of N-LDL during short-term incubations but reached statistical significance (P < 0.05) when LDL subfractions were incubated with cells for 24 h. G-LDL stimulated cholesteryl ester synthesis rates in human macrophages significantly (P < 0.05) more than N-LDL from the same subject and thus may contribute to the increased prevalence of atherosclerosis in diabetic patients.
Effect of Obesity on Insulin Resistance in Normal Subjects and Patients With NIDDM
Authors: Ludvik Bernhard , Nolan John J , Baloga Joseph , Sacks David , Olefsky Jerrold
Published: September 2013

Insulin resistance (IR) is a characteristic feature of non-insulin-dependent diabetes mellitus (NIDDM) as well as obesity, and a majority of NIDDM patients are obese. To assess the effect of obesity independent of NIDDM on IR, we studied the relationship between IR and obesity in 65 normal and 58 NIDDM subjects; we used body mass index (BMI) as a measure of obesity and glucose infusion rate (GINF) during a euglycemic hyperinsulinemic (120 mU · m−2 · min−1) glucose clamp as a measure of IR. In lean normal subjects, GINF was 57.7 ± 2.2 μmol · kg−1 · min−1 (10.4 ± 0.4 mg · kg−1 · min−1) and the lean NIDDM subjects were markedly insulin-resistant, with a GINF of 34.4 ± 2.8 μmol · kg−1 · min−1 (6.2 ± 0.5 mg · kg−1 · min−1). Obese normal subjects were also insulin-resistant compared with lean normal subjects, with a GINF of 36.1 ± 2.2 μmol · kg−1 · min−1 (6.5 ± 0.4 mg · kg−1 · min−1), and obesity caused an increase in IR in NIDDM, with a GINF of 21.1 ± 1.4 μmol · kg−1 · min−1 (3.8 ± 0.25 mg · kg−1 · min−1) in the obese NIDDM subjects. Therefore, ∼61% of the IR in obese NIDDM subjects is due to NIDDM, with 39% due to obesity, demonstrating a greater impact of NIDDM than of obesity in causing IR. The correlation between GINF and BMI was much better in normal subjects (r = −0.75) than in NIDDM subjects (r = −0.50) as was the relationship between fasting insulin level and BMI (r = −0.59 in normal subjects, r = −0.48 in NIDDM subjects). As expected, the fasting insulin level was also strongly correlated to GINF in normal subjects (r = −0.61); however, this relationship was weaker in NIDDM subjects (r = −0.46). In conclusion, 1) obesity has a major impact to cause insulin resistance in nondiabetic subjects, but the effect of obesity on IR in NIDDM is less; 2) NIDDM per se is the major contributor to IR in NIDDM; and 3) the fasting insulin level is a better surrogate marker of IR in nondiabetic subjects than in NIDDM patients.