Vitamin C Further Improves the Protective Effect of Glucagon-Like Peptide-1 on Acute Hypoglycemia-Induced Oxidative Stress,Inflammation, and Endothelial Dysfunction in Type 1 Diabetes

OBJECTIVE

To test the hypothesis that acute hypoglycemia induces endothelial dysfunction and inflammation through the generation of an oxidative stress. Moreover, to test if the antioxidant vitamin C can further improve the protective effects of glucagon-like peptide 1 (GLP-1) on endothelial dysfunction and inflammation during hypoglycemia in type 1diabetes.

RESEARCH DESIGN AND METHODS

A total of 20 type 1 diabetic patients underwent four experiments: a period of 2 h of acute hypoglycemia with or without infusion of GLP-1 or vitamin C or both. At baseline, after 1 and 2 h, glycemia, plasma nitrotyrosine, plasma 8-iso prostaglandin F2a (PGF2a), soluble intracellular adhesion molecule-1a (sICAM-1a), interleukin-6 (IL-6), and flow-mediated vasodilation were measured. At 2 h of hypoglycemia, flow-mediated vasodilation significantly decreased, while sICAM-1, 8-iso-PGF2a, nitrotyrosine, and IL-6 significantly increased. The simultaneous infusion of GLP-1 or vitamin C significantly attenuated all of these phenomena. Vitamin C was more effective. When GLP-1 and vitamin C were infused simultaneously, the deleterious effect of hypoglycemia was almost completely counterbalanced.

RESULTS

At 2 h of hypoglycemia, flow-mediated vasodilation significantly decreased, while sICAM-1, 8-iso-PGF2a, nitrotyrosine, and IL-6 significantly increased. The simultaneous infusion of GLP-1 or vitamin C significantly attenuated all of these phenomena. Vitamin C was more effective. When GLP-1 and vitamin C were infused simultaneously, the deleterious effect of hypoglycemia was almost completely counterbalanced.

CONCLUSIONS

This study shows that vitamin C infusion, during induced acute hypoglycemia, reduces the generation of oxidative stress and inflammation, improving endothelial dysfunction, in type 1 diabetes. Furthermore, the data support a protective effect of GLP-1 during acute hypoglycemia, but also suggest the presence of an endothelial resistance to the action of GLP-1, reasonably mediated by oxidative stress.Recent evidence suggests that hypoglycemia can be considered a new risk factor in favoring diabetes vascular complications (1). It has been reported that hypoglycemia produces endothelial dysfunction and inflammation (2,3), which are well-recognized pathogenic factors for vascular disease, particularly in diabetes (4). Oxidative stress is considered the key player in the pathogenesis of diabetes complications (5), and it has been suggested that hypoglycemia produces endothelial dysfunction and inflammation through oxidative stress generation both in vitro and in humans (2,3). However, clear evidence in humans is still lacking (6): particularly, what is still missed is the evidence that by using an antioxidant, the elevation of the markers of oxidative stress induced by hypoglycemia can be reversed.Recently, a possible beneficial effect of glucagon-like peptide 1 (GLP-1) analogs in the management of type 1 diabetes has been suggested (7,8). GLP-1 and its analogs, in addition to their insulin-tropic action in alleviating hyperglycemia, have beneficial effects in protecting progressive impairment of pancreatic β-cell function, preservation of β-cell mass, and suppression of glucagon secretion, gastric emptying, and appetite, all characteristics that could be beneficial for the management of type 1 diabetes (7,8).Apart from the well-documented incretin effect of GLP-1, its role in the cardiovascular system also arouses interest. GLP-1 effects on the cardiovascular system may include a direct action on the endothelium, where the presence of specific receptors for GLP-1 has been demonstrated (9). Consistently, GLP-1 has been demonstrated to improve endothelial function in diabetes (10,11), possibly increasing the antioxidant defenses of the endothelium (12) and decreasing oxidative stress generation (11). Recently, we have reported that in type 1 diabetes, during induced-hypoglycemia, GLP-1 can partially protect endothelial function and partially decrease the appearance of inflammation, reducing, concomitantly, the level of several markers of oxidative stress (13). However, it is worthy of interest that in type 2 diabetes, hyperglycemia induces an endothelial resistance to the action of GLP-1, oxidative stress being the mediator of such a phenomenon (11).The aim of this study was to test, in patients with type 1 diabetes, whether 1) the concomitant infusion of an antioxidant, vitamin C, can protect endothelial function and reduce the generation of oxidative stress and inflammation during acute induced-hypoglycemia and 2) the effects of GLP-1 and vitamin C on both endothelial dysfunction and oxidative stress induced by acute hypoglycemia were additive.     

The Role of Adjunctive Exenatide Therapy in Pediatric Type 1 Diabetes

OBJECTIVE

Exenatide improves postprandial glycemic excursions in type 2 diabetes. Exenatide could benefit type 1 diabetes as well. We aimed to determine an effective and safe glucose-lowering adjuvant exenatide dose in adolescents with type 1 diabetes.

RESEARCH DESIGN AND METHODS

Eight subjects completed a three-part double-blinded randomized controlled study of premeal exenatide. Two doses of exenatide (1.25 and 2.5 μg) were compared with insulin monotherapy. Prandial insulin dose was reduced by 20%. Gastric emptying and hormones were analyzed for 300 min postmeal.

RESULTS

Treatment with both doses of exenatide versus insulin monotherapy significantly reduced glucose excursions over 300 min (P < 0.0001). Exenatide administration failed to suppress glucagon but delayed gastric emptying (P < 0.004).

CONCLUSIONS

Adjunctive exenatide therapy reduces postprandial hyperglycemia in adolescents with type 1 diabetes. This reduction in glucose excursion occurs despite reduction in insulin dose. We suggest that exenatide has therapeutic potential as adjunctive therapy in type 1 diabetes.Intensive insulin therapy delays/prevents complications associated with type 1 diabetes (1,2). However, insulin monotherapy fails to achieve normoglycemia (3). Postprandial hyperglycemia and hypoglycemia (4,5) continue to create impediments to management. Even the closed-loop system fails to normalize postprandial hyperglycemia (6). Additional therapies to insulin are needed to achieve optimal glycemic control.Glucagon-like peptide (GLP)-1 is an incretin secreted in response to nutrient ingestion (7). Physiological GLP-1 enhances insulin secretion, delays gastric emptying, and suppresses glucagon. But because of its short half-life (8), it is unsuitable for clinical application.Exenatide is a long-acting GLP-1 receptor agonist and acts similarly to native GLP-1 (9). Exenatide is effective in decreasing postprandial hyperglycemia in type 2 diabetes (10). However, there are few studies using exenatide in type 1 diabetes and none in adolescents. The objective of our study was to examine the effect of adjuvant premeal exenatide and insulin on postprandial glucose in type 1 diabetes and establish an effective and safe glucose-lowering dose.     

The possible protective role of glucagon-like peptide 1 on endothelium during the meal and evidence for an "endothelial resistance" to glucagon-like peptide 1 in diabetes

OBJECTIVE

Glucagon-like peptide 1 (GLP-1) stimulates insulin secretion. However, GLP-1 also improves endothelial function in diabetes.

RESEARCH DESIGN AND METHODS

Sixteen type 2 diabetic patients and 12 control subjects received a meal, an oral glucose tolerance test (OGTT), and two hyperglycemic clamps, with or without GLP-1. The clamps were repeated in diabetic patients after 2 months of strict glycemic control.

RESULTS

During the meal, glycemia, nitrotyrosine, and plasma 8-iso prostaglandin F2α (8-iso-PGF2a) remained unchanged in the control subjects, whereas they increased in diabetic patients. Flow-mediated vasodilation (FMD) decreased in diabetes, whereas GLP-1 increased in both groups. During the OGTT, an increase in glycemia, nitrotyrosine, and 8-iso-PGF2a and a decrease in FMD were observed at 1 h in the control subjects and at 1 and 2 h in the diabetic patients. In the same way, GLP-1 increased in both groups at the same levels of the meal. During the clamps, in both the control subjects and the diabetic patients, a significant increase in nitrotyrosine and 8-iso-PGF2a and a decrease in FMD were observed, effects that were significantly reduced by GLP-1. After improved glycemic control, hyperglycemia during the clamps was less effective in producing oxidative stress and endothelial dysfunction and the GLP-1 administration was most effective in reducing these effects.

CONCLUSIONS

Our data suggest that during the meal GLP-1 can simultaneously exert an incretin effect on insulin secretion and a protective effect on endothelial function, reasonably controlling oxidative stress generation. The ability of GLP-1 in protecting endothelial function seems to depend on the level of glycemia, a phenomenon already described for insulin secretion.Oral administration of glucose is a more potent secretory stimulus for insulin than its intravenous infusion (1). This observation gave rise to the “incretin effect” concept, i.e., stimulation of insulin secretion as a response to food before an increase in blood glucose levels. An incretin hormone is the glucagon-like peptide 1 (GLP-1).Type 2 diabetes mellitus is increasing all over the world. Patients with diabetes have an increased risk of cardiovascular disease. Recently, much attention has been paid to evidence that abnormalities of the postprandial state are important contributing factors to the development of atherosclerosis, even in diabetes (2). In diabetic subjects, the combination of postprandial hyperglycemia and postprandial hypertriglyceridemia has been recently proposed as an independent risk factor for cardiovascular disease (2).The response-to-injury hypothesis of atherosclerosis states that the initial damage affects the arterial endothelium, leading to endothelial dysfunction (3). Indeed, endothelial dysfunction has been demonstrated in patients with diabetes, and hyperglycemia has been implicated as a cause of endothelial dysfunction in normal and diabetic subjects (2). It has been suggested that hyperglycemia induces an endothelial dysfunction through the production of an oxidative stress (2).GLP-1 is now being used in clinics to enhance insulin secretion and reduce body weight in patients with type 2 diabetes mellitus (4), in whom a defect of GLP-1 secretion/action in response to the meal has often been reported (5). GLP-1 has been shown to lower postprandial and fasting glucose and HbA_1c, to suppress the elevated glucagon level, and to stimulate glucose-dependent insulin synthesis and secretion (4).Apart from the well-documented incretin effect of GLP-1, its role in the cardiovascular system also arouses interest. GLP-1 effects on the cardiovascular system may include a direct action on the endothelium, where the presence of specific receptors for GLP-1 has been demonstrated (6). GLP-1 has been demonstrated to improve endothelial function in diabetes (7). However, the explanation of why GLP-1 may have such a relevant physiologic role on cardiovascular system still remains unknown. A possible explanation would be to consider GLP-1 as an endogenous protective factor for the vascular system when this protection is especially needed: during a meal. As pointed out by Zilversmit (8) many years ago, atherosclerosis could be considered to be a prandial phenomenon. Therefore, it is clearly plausible that GLP-1, on the one hand, can help during a meal (glucose homeostasis, appetite control, fat metabolism), and on the other, can protect the endothelium against the possible damaging effect of the meal. This protective effect should be exerted improving the antioxidant defenses of the endothelium (9), thereby protecting the vascular system against the oxidative stress that increases after ingesting a meal (2).The aim of this study is to prove that GLP-1 physiologically protects the endothelial function during a meal and, more specifically, protects the endothelial function from the hyperglycemia-induced alterations, and that this effect is mediated by lowering oxidative stress. Moreover, a further aim is to explore this aspect in diabetes.     

Adding Once-Daily Lixisenatide for Type 2 Diabetes Inadequately Controlled by Established Basal Insulin: A 24-week,randomized, placebo-controlled comparison (GetGoal-L)

OBJECTIVE

To examine the efficacy and safety of adding the once-daily glucagon-like peptide-1 receptor agonist (GLP-1RA) lixisenatide to established basal insulin therapy alone or together with metformin, in people with type 2 diabetes and elevated glycated hemoglobin (HbA_1c).

RESEARCH DESIGN AND METHODS

We conducted a double-blind, parallel-group, placebo-controlled trial. Patients (n = 495) with established basal insulin therapy but inadequate glycemic control were randomized to add lixisenatide 20 μg or placebo for 24 weeks. Basal insulin dosage was unchanged except to limit hypoglycemia. HbA_1c reduction from baseline was the primary end point.

RESULTS

Mean duration of diabetes was 12.5 years, duration of insulin use was 3.1 years, insulin dosage was 55 units/day, and baseline HbA_1c was 8.4%. With lixisenatide, the placebo-corrected change of HbA_1c from baseline was –0.4% (95% CI –0.6 to –0.2; P = 0.0002), and mean HbA_1c at end point was 7.8%. HbA_1c <7.0% (53 mmol/mol) was attained by more lixisenatide (28%) than placebo (12%; P < 0.0001) participants. Lixisenatide reduced plasma glucose levels after a standardized breakfast (placebo-corrected reduction, –3.8 mmol/L; P < 0.0001); seven-point glucose profiles showed a reduction persisting through the day. Reductions in body weight (placebo corrected, –1.3 kg; P < 0.0001) and insulin dosage (–3.7 units/day; P = 0.012) were greater with lixisenatide. Main adverse events (AEs) with lixisenatide were gastrointestinal. Symptomatic hypoglycemia was 28% for lixisenatide and 22% for placebo; 4 of 328 subjects (1.2%) had severe hypoglycemia with lixisenatide vs. 0 of 167 with placebo.

CONCLUSIONS

By improving HbA_1c and postprandial hyperglycemia without weight gain in type 2 diabetes with inadequate glycemic control despite stable basal insulin, lixisenatide may provide an alternative to rapid-acting insulin or other treatment options.In type 2 diabetes, additional therapies are needed over time to maintain acceptable glycemic control (1–3). When lifestyle measures and oral antihyperglycemic agents are no longer sufficient, the addition of basal insulin optimized by systematic titration of dosage can restore glycated hemoglobin (HbA_1c) to 7.0% for 50–60% of people with type 2 diabetes (2,4,5). However, some people do not initially achieve this glycemic target with basal insulin plus oral therapy, and others experience later deterioration of control (6–9). Further therapy, especially for postprandial hyperglycemia, is then needed. A traditional option has been to add one or more injections of prandial insulin (10), but adding a glucagon-like peptide-1 receptor agonist (GLP-1RA) is a recently proposed alternative that may improve glycemic control without additional weight gain and, perhaps, with less hypoglycemia. Drugs of this class have effects that complement those of basal insulin; they potentiate endogenous insulin responses to hyperglycemia, suppress inappropriately elevated glucagon secretion, and favor weight loss by promoting satiety (11,12). In addition, GLP-1RAs can slow gastric emptying, further blunting postprandial hyperglycemia. However, slowing of gastric emptying appears to be greater with short-acting than with long-acting GLP-1RAs (13), possibly related to the observation that, with time, continuous exposure of GLP-1 leads to a reduction in its effect on gastric emptying (14).Lixisenatide is a novel GLP-1RA that, like other drugs of its class, has demonstrated significant improvements in glycemic control, low rates of hypoglycemia, and a beneficial effect on weight (15–17). Lixisenatide taken once daily (15) improves HbA_1c levels by reducing fasting plasma glucose (FPG) and has robust postprandial glucose (PPG) effects (18,19). Lixisenatide was granted marketing authorization by the European Medicines Agency in February 2013 (20). The objective of this study was to examine the efficacy and safety of adding once-daily lixisenatide to established basal insulin therapy (dosage maintained except for the avoidance of hypoglycemia), alone or together with metformin, in people with long-duration type 2 diabetes and inadequate glycemic control.     

Potential of Albiglutide, a Long-Acting GLP-1 Receptor Agonist, in Type 2 Diabetes: A randomized controlled trial exploring weekly, biweekly, and monthly dosing

OBJECTIVE

To evaluate the efficacy, safety, and tolerability of incremental doses of albiglutide, a long-acting glucagon-like peptide-1 receptor agonist, administered with three dosing schedules in patients with type 2 diabetes inadequately controlled with diet and exercise or metformin monotherapy.

RESEARCH DESIGN AND METHODS

In this randomized multicenter double-blind parallel-group study, 356 type 2 diabetic subjects with similar mean baseline characteristics (age 54 years, diabetes duration 4.9 years, BMI 32.1 kg/m², A1C 8.0%) received subcutaneous placebo or albiglutide (weekly [4, 15, or 30 mg], biweekly [15, 30, or 50 mg], or monthly [50 or 100 mg]) or exenatide twice daily as an open-label active reference (per labeling in metformin subjects only) over 16 weeks followed by an 11-week washout period. The main outcome measure was change from baseline A1C of albiglutide groups versus placebo at week 16.

RESULTS

Dose-dependent reductions in A1C were observed within all albiglutide schedules. Mean A1C was similarly reduced from baseline by albiglutide 30 mg weekly, 50 mg biweekly (every 2 weeks), and 100 mg monthly (−0.87, −0.79, and −0.87%, respectively) versus placebo (−0.17%, P < 0.004) and exenatide (−0.54%). Weight loss (−1.1 to −1.7 kg) was observed with these three albiglutide doses with no significant between-group effects. The incidence of gastrointestinal adverse events in subjects receiving albiglutide 30 mg weekly was less than that observed for the highest biweekly and monthly doses of albiglutide or exenatide.

CONCLUSIONS

Weekly albiglutide administration significantly improved glycemic control and elicited weight loss in type 2 diabetic patients, with a favorable safety and tolerability profile.Early intervention to improve glycemic control reduces microvascular complications in type 2 diabetes (1–4) and may provide long-term macrovascular benefits (5). Despite numerous available therapies, over half of patients with type 2 diabetes are unable to achieve the American Diabetes Association (ADA) target A1C level (<7%) (6–8). Moreover, weight gain and treatment-induced hypoglycemic episodes (9,10) are major barriers to achieving glycemic control (10).Antidiabetic therapies based on glucagon-like peptide-1 (GLP-1) retain the ability of native GLP-1 to stimulate glucose-dependent insulin secretion and suppress inappropriately elevated glucagon secretion (11,12). Native GLP-1 also slows gastric emptying and reduces food intake, which leads to modest weight loss (11). However, native GLP-1 is rapidly inactivated (half-life 1–2 min) by dipeptidyl peptidase-4 (DPP-4), limiting its therapeutic potential (13). Exenatide (half-life 2.4 h) improves glycemic control in combination with metformin, a sulfonylurea, or a thiazolidinedione (14–18). Despite modest weight loss and improved glycemic control, gastrointestinal (GI) intolerability and twice-daily administration may lead to discontinuation (19).Albiglutide (formerly known as albugon) is a GLP-1 receptor agonist developed through the fusion of two repeats of human GLP-1 (7–36) molecules to recombinant human albumin (20). The GLP-1 dimer was used to avoid potential reductions of the interaction of the GLP-1 moiety of the monomer with its receptor in the presence of albumin. A single amino acid substitution (ala8→gly) renders the molecule resistant to DPP-4. The structure of albiglutide provides an extended half-life (∼5 days), which may allow weekly or less frequent dosing. Furthermore, albiglutide is relatively impermeant to the central nervous system (21), which may have implications for GI tolerability. In nonclinical studies, albiglutide stimulated cAMP production through the GLP-1 receptor and induced insulin secretion from INS-1 cells in vitro and in animal models (21–22). It also delayed gastric emptying and reduced food intake in rodents (21–23).This study was designed to explore a wide range of doses (4–100 mg) and schedules (weekly to monthly) to assess glycemic control and adverse event profiles for albiglutide. Exenatide was included as an open-label reference to provide clinical perspective for a GLP-1 receptor agonist.     

Associations between media consumption habits, physical activity, socioeconomic status, and glycemic control in children, adolescents, and young adults with type 1 diabetes

OBJECTIVE

To evaluate the relationship between media consumption habits, physical activity, socioeconomic status, and glycemic control in youths with type 1 diabetes.

RESEARCH DESIGN AND METHODS

In the cross-sectional study, self-report questionnaires were used to assess media consumption habits, physical activity, and socioeconomic status in 296 children, adolescents, and young adults with type 1 diabetes. Clinical data and HbA_1c levels were collected. Risk factors were analyzed by multiple regression.

RESULTS

Youths with type 1 diabetes (aged 13.7 ± 4.1 years, HbA_1c 8.7 ± 1.6%, diabetes duration 6.1 ± 3.3 years) spent 2.9 ± 1.8 h per day watching television and using computers. Weekly physical activity was 5.1 ± 4.5 h. Multiple regression analysis identified diabetes duration, socioeconomic status, and daily media consumption time as significant risk factors for glycemic control.

CONCLUSIONS

Diabetes duration, socioeconomic status, and daily media consumption time, but not physical activity, were significant risk factors for glycemic control in youths with type 1 diabetes.The pivotal Diabetes Control and Complications Trial (DCCT) and Epidemiology of Diabetes Interventions and Complications (EDIC) study demonstrate that poor glycemic control is associated with an increased risk of developing complications in type 1 diabetes (1). Various factors contributing to glycemic control have been identified (2). Immutable parameters such as age, sex, diabetes duration, and socioeconomic status have a major effect on metabolic control (2–6). Lower socioeconomic status is an important determinant for poor glycemic control (4,5). Modifiable factors influencing metabolic control are diabetes-related knowledge, frequency of blood glucose monitoring, and daily insulin dose (3,4,6,7). Lastly, psychosocial parameters are important in achieving good glycemic control (3–5,8–10). The influence of physical activity on metabolic control is unclear (9,11,12).Recent research addresses the influence of modern life habits on general health. Youths spend more and more time watching television and using computers. Many studies suggest that sedentary behaviors such as watching television lead to obesity in children (13,14). In one study in youths with type 1 diabetes, Margeirsdottir et al. (15) showed that poor metabolic control was associated with extensive television watching. However, the authors did not examine other covariables, such as socioeconomic status, which is associated with both glycemic control and media consumption (4,5,16,17). Hence, the aim of this study was to examine the impact of media consumption habits, physical activity, and socioeconomic status on glycemic control in youths with type 1 diabetes.     

Effectiveness of a Computerized Insulin Order Template in General Medical Inpatients With Type 2 Diabetes: A cluster randomized trial

OBJECTIVE

To determine whether an electronic order template for basal-bolus insulin ordering improves mean blood glucose in hospitalized general medical patients with hyperglycemia and type 2 diabetes.

RESEARCH DESIGN AND METHODS

We randomly assigned internal medicine resident teams on acute general medical floors to the use of an electronic insulin order template or usual insulin ordering. We measured diabetes care parameters for 1 month on all patients with type 2 diabetes and blood glucose <60 mg/dl or >180 mg/dl treated by these physicians.

RESULTS

Intervention group patients (n = 65) had mean glucose of 195 ± 66 mg/dl. Control group patients (n = 63) had mean glucose of 224 ± 57 mg/dl (P = 0.004). In the intervention group, there was no increase in hypoglycemia.

CONCLUSIONS

Access to a computer insulin order template was associated with improved mean glucose levels without increasing hypoglycemia in patients with type 2 diabetes.Physiological, basal-bolus insulin prescribing is safe, effective (1), and the standard of care in hospitalized patients with type 2 diabetes and hyperglycemia (2). Yet only about half of such patients are prescribed basal insulin in the hospital (3). Order templates to support basal-bolus insulin prescribing (usually as part of a comprehensive inpatient diabetes quality improvement program) have been effective in improving glycemia in observational trials (4–8). Randomized trials have shown more modest effects (9,10). Knowledge of appropriate insulin ordering is a barrier to ordering basal-bolus insulin among inpatient providers (11–13).We tested the hypothesis that giving internal medicine residents access to an electronic insulin order template would be more effective than usual insulin ordering in lowering mean blood glucose in medical inpatients with type 2 diabetes.     

Whole-blood tissue factor procoagulant activity is elevated in type 1 diabetes: effects of hyperglycemia and hyperinsulinemia

OBJECTIVE

To determine tissue factor procoagulant activity (TF-PCA) in patients with type 1 diabetes and to examine effects of hyperglycemia and hyperglycemia plus hyperinsulinemia on TF-PCA.

RESEARCH DESIGN AND METHODS

We have determined circulating TF-PCA and other coagulation factors under basal (hyperglycemic) conditions, after acute correction of hyperglycemia, in response to 24 h of selective hyperglycemia, and in response to 24 h of hyperglycemia plus hyperinsulinemia in nine type 1 diabetic patients and in seven nondiabetic control subjects.

RESULTS

As shown previously in patients with type 2 diabetes, basal TF-PCA and plasma coagulation factor VIIa (FVIIa) were higher in patients with type 1 diabetes than in nondiabetic control subjects. However, in contrast with type 2 diabetes, normalizing glucose did not decrease the elevated TF-PCA levels, and raising glucose or glucose plus insulin levels did not increase TF-PCA.

CONCLUSIONS

Patients with type 1 diabetes have elevated circulating TF-PCA and FVIIa levels and are in a procoagulant state that may predispose them to acute cardiovascular events. The mechanisms regulating TF-PCA in patients with type 1 and type 2 diabetes are different and should be further explored.Type 1 diabetes mellitus (T1DM) is associated with increased risk for atherosclerotic vascular disease (1). There are several well-recognized factors responsible for this enhanced risk, including hypertension, atherogenic dyslipidemia, smoking, and renal disease. Additional putative risk factors include the alterations in platelet function, plasma coagulation factors, and the fibrinolytic system that indicates a prothrombotic state (2–4). Thrombosis is a key factor in acute events associated with atherosclerotic vascular disease, including myocardial infarction, stroke, and peripheral arterial disease. Tissue factor (TF) is the primary physiological initiator of blood coagulation and thrombosis (5,6). The original concept that TF was present only in the adventitia of blood vessels and in atherosclerotic plaques, and initiates blood coagulation only when vessel walls were injured or plaques fissured (7), has recently been broadened by the demonstration that, in addition, there is a circulating pool of TF in blood that is thrombogenic (5,6,8–10).We and others have previously shown that patients with type 2 diabetes mellitus (T2DM) have elevated levels of circulating TF procoagulant activity (TF-PCA) and are in a procoagulant state (11,12). Further, we have reported that raising blood insulin levels, and especially raising blood glucose and insulin levels together to levels frequently seen in diabetic patients, increased TF-PCA and thrombin generation in patients with T2DM and in nondiabetic volunteers (11,13). These findings support the notion that hyperglycemia and hyperinsulinemia are likely to contribute to the procoagulant state in patients with T2DM and to their predisposition for acute cardiovascular events. On the other hand, there is currently no information on circulating levels of TF-PCA and TF responses to hyperglycemia and hyperinsulinemia in patients with T1DM who are at comparable, if not greater, risk for cardiovascular events than patients with T2DM (4). Further, whether selective hyperglycemia (i.e., hyperglycemia without hyperinsulinemia) affects TF-PCA is not known. The reason is that to produce selective hyperglycemia in nondiabetic patients or in T2DM patients, somatostatin needs to be infused together with glucose to prevent hyperglycemia-induced hyperinsulinemia. Somatostatin, however, was found to have its own effects on TF-PCA (14). In contrast, in C-peptide–negative patients with T1DM, selective hyperglycemia can be produced without somatostatin. The objectives of this study, therefore, were to investigate in patients with T1DM levels of TF-PCA and other blood coagulation factors under basal (overnight fasted) conditions and in response to 24 h of selective hyperglycemia or combined hyperglycemia plus hyperinsulinemia.     

Effects of a d-Xylose Preload With or Without Sitagliptin on Gastric Emptying,Glucagon-Like Peptide-1, and Postprandial Glycemia in Type 2 Diabetes

OBJECTIVE

Macronutrient “preloads” can reduce postprandial glycemia by slowing gastric emptying and stimulating glucagon-like peptide-1 (GLP-1) secretion. An ideal preload would entail minimal additional energy intake and might be optimized by concurrent inhibition of dipeptidyl peptidase-4 (DPP-4). We evaluated the effects of a low-energy d-xylose preload, with or without sitagliptin, on gastric emptying, plasma intact GLP-1 concentrations, and postprandial glycemia in type 2 diabetes.

RESEARCH DESIGN AND METHODS

Twelve type 2 diabetic patients were studied on four occasions each. After 100 mg sitagliptin (S) or placebo (P) and an overnight fast, patients consumed a preload drink containing either 50 g d-xylose (X) or 80 mg sucralose (control [C]), followed after 40 min by a mashed potato meal labeled with ¹³C-octanoate. Blood was sampled at intervals. Gastric emptying was determined.

RESULTS

Both peak blood glucose and the amplitude of glycemic excursion were lower after PX and SC than PC (P < 0.01 for each) and were lowest after SX (P < 0.05 for each), while overall blood glucose was lower after SX than PC (P < 0.05). The postprandial insulin-to-glucose ratio was attenuated (P < 0.05) and gastric emptying was slower (P < 0.01) after d-xylose, without any effect of sitagliptin. Plasma GLP-1 concentrations were higher after d-xylose than control only before the meal (P < 0.05) but were sustained postprandially when combined with sitagliptin (P < 0.05).

CONCLUSIONS

In type 2 diabetes, acute administration of a d-xylose preload reduces postprandial glycemia and enhances the effect of a DPP-4 inhibitor.Therapeutic strategies directed at reducing postprandial glycemia are of fundamental importance in the management of type 2 diabetes (1). For patients with mild-to-moderate hyperglycemia, postprandial blood glucose is a better predictor of HbA_1c than fasting blood glucose (2).Both gastric emptying and the action of the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are major determinants of postprandial glucose excursions (3). Gastric emptying determines the rate of nutrient delivery to the small intestine, accounting for approximately one-third of the variation in the initial rise in glycemia after oral glucose in both healthy subjects (4) and those with type 2 diabetes (5). GLP-1 and GIP, released predominantly from the distal and proximal gut, respectively, are the known mediators of the incretin effect, whereby much more insulin is stimulated by enteral compared with intravenous glucose (6). In type 2 diabetes, the incretin effect is impaired (7), related at least partly to a diminished insulinotropic effect of GIP, while that of GLP-1 is preserved (8). In addition, GLP-1 slows gastric emptying (9), suppresses glucagon secretion (10), and reduces energy intake (11). Therefore, incretin-based therapies for diabetes have hitherto focused on GLP-1.One promising strategy to stimulate endogenous GLP-1 is the “preload” concept, which involves administration of a small load of macronutrient at a fixed interval before a meal so that the presence of nutrients in the small intestine induces the release of gut peptides, including GLP-1, to slow gastric emptying and improve the glycemic response to the subsequent meal. Fat (12) and protein (13) preloads achieve these goals but entail additional energy intake. We recently demonstrated in healthy subjects the potential for poorly absorbed sweeteners, which yield little energy, to stimulate GLP-1 secretion and slow gastric emptying (14).d-Xylose is a pentose sugar, which is incompletely absorbed by passive diffusion in human duodenum and jejunum (15), with the remainder delivered to the ileum and the colon, where bacterial fermentation occurs, producing hydrogen that can be detected in the breath (16). We recently showed that oral consumption of d-xylose stimulates GLP-1 secretion to a greater and more sustained degree than glucose in healthy older subjects (17), consistent with the principle that the length and region of small intestine exposed to carbohydrate are important determinants of GLP-1 release (18). D-Xylose also slowed gastric emptying compared with water, with efficacy similar to that of the glucose load (17).Intact GLP-1 is short-lived in the circulation largely because of rapid degradation by the enzyme dipeptidyl peptidase-4 (DPP-4) (19), and orally administered DPP-4 inhibitors, such as sitagliptin, increase postprandial plasma concentrations of intact GLP-1 (20). However, the concept of stimulating endogenous GLP-1 with enteral nutrients and then optimizing its action with a DPP-4 inhibitor has received little attention. Moreover, little consideration has been given as to whether the composition of the diet influences the efficacy of DPP-4 inhibition to lower postprandial blood glucose.The current study was designed to determine, in patients with type 2 diabetes, whether a d-xylose preload would slow gastric emptying, stimulate GLP-1 secretion, and improve postprandial glycemia and whether these effects could be enhanced by DPP-4 inhibition.     

Effect of continuous glucose monitoring on hypoglycemia in type 1 diabetes

OBJECTIVE

To assess the impact of continuous glucose monitoring on hypoglycemia in people with type 1 diabetes.

RESEARCH DESIGN AND METHODS

In this randomized, controlled, multicenter study, 120 children and adults on intensive therapy for type 1 diabetes and a screening level of glycated hemoglobin A_1c (HbA_1c) <7.5% were randomly assigned to a control group performing conventional home monitoring with a blood glucose meter and wearing a masked continuous glucose monitor every second week for five days or to a group with real-time continuous glucose monitoring. The primary outcome was the time spent in hypoglycemia (interstitial glucose concentration <63 mg/dL) over a period of 26 weeks. Analysis was by intention to treat for all randomized patients.

RESULTS

The time per day spent in hypoglycemia was significantly shorter in the continuous monitoring group than in the control group (mean ± SD 0.48 ± 0.57 and 0.97 ± 1.55 h/day, respectively; ratio of means 0.49; 95% CI 0.26–0.76; P = 0.03). HbA_1c at 26 weeks was lower in the continuous monitoring group than in the control group (difference −0.27%; 95% CI −0.47 to −0.07; P = 0.008). Time spent in 70 to 180 mg/dL normoglycemia was significantly longer in the continuous glucose monitoring group compared with the control group (mean hours per day, 17.6 vs. 16.0, P = 0.009).

CONCLUSIONS

Continuous glucose monitoring was associated with reduced time spent in hypoglycemia and a concomitant decrease in HbA_1c in children and adults with type 1 diabetes.The benefits of intensive treatment of type 1 diabetes, established almost 20 years ago (1), are difficult to achieve, despite the increased use of insulin analogs and insulin pumps, with only a minority of patients maintaining their glycated hemoglobin A_1c (HbA_1c) within the target range (2). Intensive insulin treatment and lower HbA_1c increase exposure to hypoglycemia (3,4). The risk of hypoglycemia is even higher in children and adolescents (5,6) and increases with the duration of diabetes (7). Frequent hypoglycemia is associated with hypoglycemia unawareness (8,9), which may in turn lead to reduced adherence to therapeutic decisions (10). Finally, hypoglycemia may be associated with permanent damage to the central nervous system (11) and may permanently influence cognitive functions in children (12) but not in adults (13).Recently, devices for real-time continuous glucose monitoring have been introduced to aid self-management of glycemic control and have been shown to improve HbA_1c levels in people with type 1 diabetes (14–17). In clinical practice recommendations, it has also been suggested that continuous glucose monitoring is especially useful in patients with hypoglycemia unawareness and/or frequent episodes of hypoglycemia (18). However, the hypoglycemia preventive effect of continuous glucose monitoring has not been established. Therefore, we designed a randomized, controlled, multicenter clinical trial to evaluate the effect of continuous glucose monitoring on hypoglycemia in children and adults with type 1 diabetes.     

Efficacy and Safety of the Human Glucagon-Like Peptide-1 Analog Liraglutide in Combination With Metformin and Thiazolidinedione in Patients With Type 2 Diabetes (LEAD-4 Met+TZD)

OBJECTIVE

To determine the efficacy and safety of liraglutide (a glucagon-like peptide-1 receptor agonist) when added to metformin and rosiglitazone in type 2 diabetes.

RESEARCH DESIGN AND METHODS

This 26-week, double-blind, placebo-controlled, parallel-group trial randomized 533 subjects (1:1:1) to once-daily liraglutide (1.2 or 1.8 mg) or liraglutide placebo in combination with metformin (1 g twice daily) and rosiglitazone (4 mg twice daily). Subjects had type 2 diabetes, A1C 7–11% (previous oral antidiabetes drug [OAD] monotherapy ≥3 months) or 7–10% (previous OAD combination therapy ≥3 months), and BMI ≤45 kg/m².

RESULTS

Mean A1C values decreased significantly more in the liraglutide groups versus placebo (mean ± SE −1.5 ± 0.1% for both 1.2 and 1.8 mg liraglutide and −0.5 ± 0.1% for placebo). Fasting plasma glucose decreased by 40, 44, and 8 mg/dl for 1.2 and 1.8 mg and placebo, respectively, and 90-min postprandial glucose decreased by 47, 49, and 14 mg/dl, respectively (P < 0.001 for all liraglutide groups vs. placebo). Dose-dependent weight loss occurred with 1.2 and 1.8 mg liraglutide (1.0 ± 0.3 and 2.0 ± 0.3 kg, respectively) (P < 0.0001) compared with weight gain with placebo (0.6 ± 0.3 kg). Systolic blood pressure decreased by 6.7, 5.6, and 1.1 mmHg with 1.2 and 1.8 mg liraglutide and placebo, respectively. Significant increases in C-peptide and homeostasis model assessment of β-cell function and significant decreases in the proinsulin-to-insulin ratio occurred with liraglutide versus placebo. Minor hypoglycemia occurred more frequently with liraglutide, but there was no major hypoglycemia. Gastrointestinal adverse events were more common with liraglutide, but most occurred early and were transient.

CONCLUSIONS

Liraglutide combined with metformin and a thiazolidinedione is a well-tolerated combination therapy for type 2 diabetes, providing significant improvements in glycemic control.Type 2 diabetes is characterized by insulin resistance and progressive β-cell failure. Treatment often must be intensified over time, usually by a combination of agents that address both insulin resistance and β-cell dysfunction (1,2). However, several available therapies increase the risk for hypoglycemia and weight gain, which may reduce patient adherence and lead to poor glycemic control (3).Glucagon-like peptide-1 (GLP-1) stimulates insulin secretion and suppression of glucagon secretion in a glucose-dependent manner, delays gastric emptying, and decreases appetite (4). GLP-1 is rapidly degraded by dipeptidyl peptidase-4 (4). Liraglutide is a human GLP-1 analog with 97% homology to native GLP-1 (5). Liraglutide has a half-life in humans of 13 h compared with 1–2 min for native GLP-1, making liraglutide suitable as a once-daily treatment for patients with type 2 diabetes (6).In previously published phase 3 trials (the Liraglutide Effect and Action in Diabetes [LEAD] Program), treatment with liraglutide produced substantial and clinically significant reductions in A1C and fasting and postprandial glucose (PPG) levels, with a low risk of hypoglycemia, and moderate weight loss (7–10). Liraglutide treatment alone or in combination with oral antidiabetes drugs (OADs) demonstrated significantly larger A1C reductions compared with glimepiride (monotherapy) (7), rosiglitazone (in combination with a sulfonylurea) (8), and insulin glargine (in combination with metformin and sulfonylurea) (10). When initiated as monotherapy in a subgroup of previously treatment-naïve patients with type 2 diabetes, a mean A1C reduction of 1.6% was observed, with mean A1C values sustained below 7.0% over 52 weeks (7). In combination with metformin, liraglutide reduced body weight by 2–3 kg, with the majority of the weight loss being fat (11). In addition, a decrease in systolic blood pressure (SBP) has been previously demonstrated (7–10). No major hypoglycemic events occurred during the randomized treatment period when liraglutide was used as monotherapy or with metformin (7,9). The current study investigated liraglutide treatment in combination with metformin and a thiazolidinedione (TZD) (rosiglitazone) as part of the LEAD program. These three glucose-lowering agents are of particular interest, as they have complementary modes of action and are not generally associated with increased risk of hypoglycemia.     

Dipeptidyl peptidase-4 inhibitors and bone fractures: a meta-analysis of randomized clinical trials

OBJECTIVE

Thiazolidinediones and insulin are associated with a higher risk of fractures in type 2 diabetic patients. Incretin hormones increase bone density in experimental models, but the effect of dipeptidyl peptidase-4 (DPP-4) inhibitors on bone fractures has not been reported so far.

RESEARCH DESIGN AND METHODS

A meta-analysis was performed including all randomized clinical trials with a duration of at least 24 weeks, enrolling patients with type 2 diabetes, comparing DPP-4 inhibitors with placebo or active drugs.

RESULTS

Twenty-eight trials enrolling 11,880 and 9,175 patients for DPP-4 inhibitors and comparators, respectively, were included, reporting 63 fractures. DPP-4 inhibitors, compared with placebo or other treatments, were associated with a reduced risk of fractures (Mantel–Haenszel odds ratio [MH-OR] 0.60, 95% CI 0.37–0.99, P = 0.045), even after the exclusion of comparisons with thiazolidinediones or sulfonylureas (MH-OR 0.56, 0.33–0.93, P = 0.026).

CONCLUSIONS

The present meta-analysis suggests that treatment with DPP-4 inhibitors could be associated with a reduced risk of bone fractures.Type 2 diabetes is associated with an increased risk for bone fractures (1–3). The higher risk could be determined by several factors, including falls, diabetes complications, and comorbidities (2). Moreover, glucose-lowering agents such as thiazolidinediones have been reported to reduce bone density (4,5) and to increase the incidence of fractures in longer-term trials (6,7) and in epidemiologic studies (8). Insulin therapy is also associated with an increased fracture risk (9–11) despite its neutral effect on bone density (12). The increased risk of falls, due to hypoglycemia, could lead to higher fracture risk (10).Glucagon-like peptide-1 (GLP-1) has been reported to induce osteoblast differentiation (13) and inhibit osteoclastic activity (14); GLP-1 receptor agonists stimulate bone formation in rodents (15). Experimental data in animal models suggest that gastric intestinal polypeptide is also capable of increasing bone density (16,17). Drugs capable of increasing incretin levels, such as dipeptidyl peptidase-4 (DPP-4) inhibitors, could therefore exert beneficial effects on the bone.     

Personal and Relationship Challenges of Adults With Type 1 Diabetes: A qualitative focus group study

OBJECTIVE

Little is known about the psychosocial challenges of adults living with type 1 diabetes or its impact on partner relationships. This qualitative study was undertaken to gain better understanding of these issues.

RESEARCH DESIGN AND METHODS

Four focus groups were held, two with adult type 1 diabetic patients (n = 16) and two with partners (n = 14). Two broad questions were posed: “What are the emotional and interpersonal challenges you have experienced because you have (your partner has) type 1 diabetes?” and “How does the fact that you have (your partner has) type 1 diabetes affect your relationship with your partner, positively and/or negatively?” Sessions were recorded and transcribed, and analyzed by a team of four researchers, using constant comparative methods to identify core domains and concepts.

RESULTS

Four main domains were identified: 1) impact of diabetes on the relationship, including level of partner involvement, emotional impact of diabetes on the relationship, and concerns about child-rearing; 2) understanding the impact of hypoglycemia; 3) stress of potential complications; and 4) benefits of technology. Themes suggest that, although partner involvement varies (very little to significant), there exists significant anxiety about hypoglycemia and future complications and sources of conflict that may increase relationship stress. Partner support is highly valued, and technology has a positive influence.

CONCLUSIONS

Adults with type 1 diabetes face unique emotional and interpersonal challenges. Future research should focus on gaining a better understanding of how they cope and the effect of psychosocial stressors and coping on adherence, quality of life, and glycemic control.Studies of people with type 1 diabetes have focused on children and young adults and describe many emotional and interpersonal challenges. Youth are at increased risk for psychiatric, eating, and substance abuse disorders, interpersonal problems, nonadherence, and poor quality of life (1,2). “Emerging” adults must address the responsibilities of intensive self-care (e.g., healthcare access) while managing normative challenges (e.g., jobs) (3,4).Little is known about common psychosocial challenges of adults with type 1 diabetes. Type 1 diabetes is a challenging disease. Those diagnosed as children live with the disease for most of their lives. All are vulnerable to complications that affect quality of life (5). Self-care is demanding, requiring frequent testing, insulin adjustment, and hypervigilance against hypoglycemia. Studies show the negative effects on quality of life of male sexual dysfunction (6) and of frequent or traumatic severe hypoglycemia episodes (7). The odds of depression are two times higher for adults with type 1 diabetes (8), and disordered eating and insulin omission are concerns (9). Effective coping skills are important; they relate to better glycemic control (10,11) and regimen adherence (10,12). Personal models of type 1 diabetes that are more negative (e.g., less perceived control) relate to poorer coping and clinic attendance (13). Overall, the literature on psychosocial challenges and factors affecting the outcomes of adult type 1 diabetic patients is lacking.One area studied is the effect of family support on outcomes. Greater family conflict for youth with type 1 diabetes, and less family support for adults, predicts poorer adherence (14,15). For adults with type 2 diabetes, greater marital satisfaction relates to lower risk of developing metabolic syndrome (16), better marital quality relates to better quality of life and adherence (17–19), and nonsupportive partner behaviors relate to poorer medication adherence (20). Also, partners of people with type 2 diabetes may experience as much, or more, distress as the patient (21).One would expect similar significant effects on important relationships of adult type 1 diabetic patients. One study found that those who achieved improved glycemic control with continuous glucose monitoring also reported that their “significant other” encouraged and participated with them (22). One study of spouses of patients who had recently experienced severe hypoglycemia found greater distress and marital conflict than spouses whose partners had not, and even more fear of hypoglycemia than the patients (23). Generally, little is known about these intra- and interpersonal challenges.We adopted a qualitative approach to better understand the unique psychosocial challenges of adults with type 1 diabetes, and patient/partner perspectives on how diabetes impacts their relationships (24). We chose focus groups, not individual interviews, because data are obtained from the communication between participants, as they share experiences and comment on different perspectives. Also, sometimes participants are more open when less inhibited members explore difficult topics, and more open in a group format (25).     

Large Pre- and Postexercise Rapid-Acting Insulin Reductions Preserve Glycemia and Prevent Early- but Not Late-Onset Hypoglycemia in Patients With Type 1 Diabetes

OBJECTIVE

To examine the acute and 24-h glycemic responses to reductions in postexercise rapid-acting insulin dose in type 1 diabetic patients.

RESEARCH DESIGN AND METHODS

After preliminary testing, 11 male patients (24 ± 2 years, HbA_1c 7.7 ± 0.3%; 61 ± 3.4 mmol/mol) attended the laboratory on three mornings. Patients consumed a standardized breakfast (1 g carbohydrate ⋅ kg⁻¹ BM; 380 ± 10 kcal) and self-administered a 25% rapid-acting insulin dose 60 min prior to performing 45 min of treadmill running at 72.5 ± 0.9% VO_2peak. At 60 min postexercise, patients ingested a meal (1 g carbohydrate ⋅ kg⁻¹ BM; 660 ± 21 kcal) and administered a Full, 75%, or 50% rapid-acting insulin dose. Blood glucose concentrations were measured for 3 h postmeal. Interstitial glucose was recorded for 20 h after leaving the laboratory using a continuous glucose monitoring system.

RESULTS

All glycemic responses were similar across conditions up to 60 min postexercise. After the postexercise meal, blood glucose was preserved under 50%, but declined under Full and 75%. Thence at 3 h, blood glucose was highest under 50% (50% [10.4 ± 1.2] vs. Full [6.2 ± 0.7] and 75% [7.6 ± 1.2 mmol ⋅ L⁻¹], P = 0.029); throughout this period, all patients were protected against hypoglycemia under 50% (blood glucose ≤3.9; Full, n = 5; 75%, n = 2; 50%, n = 0). Fifty percent continued to protect patients against hypoglycemia for a further 4 h under free-living conditions. However, late-evening and nocturnal glycemia were similar; as a consequence, late-onset hypoglycemia was experienced under all conditions.

CONCLUSIONS

A 25% pre-exercise and 50% postexercise rapid-acting insulin dose preserves glycemia and protects patients against early-onset hypoglycemia (≤8 h). However, this strategy does not protect against late-onset postexercise hypoglycemia.Patients with type 1 diabetes are encouraged to engage in regular exercise as part of a healthy lifestyle (1,2). However, engaging in exercise is not without its difficulties (1). Defective glucose regulation presents a significant challenge in preventing hypoglycemia during, and particularly after, exercise (3,4). Exercise-induced hypoglycemia is both a frequent (5) and dangerous occurrence (6) and remains a major obstacle to patients who wish to engage in exercise (7).Much of the literature has focused on providing strategies to help combat hypoglycemia during, and early after, exercise (8–17), with investigations focusing on altering exercise modality (14,18), carbohydrate consumption (12,16,17), and reductions to pre-exercise, rapid-acting insulin dose (10–12,17,19). Prior to moderate-intensity, continuous, aerobic exercise, it is recommended that patients should reduce their prandial rapid-acting insulin dose by ∼75% to prevent hypoglycemia during exercise (10–12). However, despite best preserving blood glucose, it has been shown that this strategy is not fully protective against postexercise hypoglycemia (11,12). This has, in part, been attributed to iatrogenic causes (11), whereby patients administer their usual doses of rapid-acting insulin in a heightened insulin-sensitive state, potentially leading to unexpected falls in blood glucose and, consequently, hypoglycemia (11).A potential strategy to help minimize the risk of developing hypoglycemia after exercise could be to reduce the dose of rapid-acting insulin administered with the postexercise meal (20). Exercise increases the sensitivity of the body to insulin for many hours after exercise (3) and patients could be faced with a window of particularly high sensitivity around the postexercise meal, whereby greater rates of glucose uptake could occur to supplement the high metabolic priority of replenishing muscle glycogen (21). Thus, the meal consumed after exercise is important. With this in mind, it would be intuitive to reduce the amount of insulin administered with the meal consumed at this time; this may preserve glycemia and prevent postexercise hypoglycemia. Conversely, severe reductions in rapid-acting insulin dose may incur prolonged postexercise hyperglycemia, even more so if the pre-exercise dose is also reduced. However, there is a lack of data to confirm or refute these hypotheses. In addition, it would be prudent to examine the extent to which rapid-acting insulin dose adjustments may help combat late falls in glycemia after exercise, considering type 1 diabetic patients are susceptible to late-onset, postexercise hypoglycemia (3), suggested to be due to a biphasic response in glucose uptake occurring early and also late after exercise (22). Therefore, the aim of this study was to examine the acute and 24-h postexercise glycemic responses to reducing the postexercise rapid-acting insulin dose, when using the recommended pre-exercise insulin reductions, in type 1 diabetic patients.     

Hypoglycemia in Type 1 Diabetic Pregnancy: Role of preconception insulin aspart treatment in a randomized study

OBJECTIVE

A recent randomized trial compared prandial insulin aspart (IAsp) with human insulin in type 1 diabetic pregnancy. The aim of this exploratory analysis was to investigate the incidence of severe hypoglycemia during pregnancy and compare women enrolled preconception with women enrolled during early pregnancy.

RESEARCH DESIGN AND METHODS

IAsp administered immediately before each meal was compared with human insulin administered 30 min before each meal in 99 subjects (44 to IAsp and 55 to human insulin) randomly assigned preconception and in 223 subjects (113 for IAsp and 110 for human insulin) randomly assigned in early pregnancy (<10 weeks). NPH insulin was the basal insulin. Severe hypoglycemia (requiring third-party assistance) was recorded prospectively preconception (where possible), during pregnancy, and postpartum. Relative risk (RR) of severe hypoglycemia was evaluated with a gamma frailty model.

RESULTS

Of the patients, 23% experienced severe hypoglycemia during pregnancy with the peak incidence in early pregnancy. In the first half of pregnancy, the RR of severe hypoglycemia in women randomly assigned in early pregnancy/preconception was 1.70 (95% CI 0.91–3.18, P = 0.097); the RR in the second half of pregnancy was 1.35 (0.38–4.77, P = 0.640). In women randomly assigned preconception, severe hypoglycemia rates occurring before and during the first and second halves of pregnancy and postpartum for IAsp versus human insulin were 0.9 versus 2.4, 0.9 versus 2.4, 0.3 versus 1.2, and 0.2 versus 2.2 episodes per patient per year, respectively (NS).

CONCLUSIONS

These data suggest that initiation of insulin analog treatment preconception rather than during early pregnancy may result in a lower risk of severe hypoglycemia in women with type 1 diabetes.Severe hypoglycemia is common in pregnant women with type 1 diabetes, with observed rates up to 15 times those reported by the Diabetes Control and Complications Trial (1), and severe hypoglycemia occurs in 19–44% of patients treated with intensive insulin therapy during pregnancy (2). The risk of experiencing a severe event is usually highest in early pregnancy, particularly during the first trimester (3–5).The risk factors that predict severe hypoglycemic episodes during pregnancy include duration of diabetes, a history of previous severe episodes (recurrent events), hypoglycemic unawareness, a change in insulin treatment (such as regimen or dosing) or a high insulin dose, and A1C <6.5% (4,6,7). However, because normoglycemia is universally recommended in diabetic pregnancy (8,9), with A1C levels between 4.0 and 6.0% advocated to optimize pregnancy outcome (10,11), minimizing the risk of severe hypoglycemia is a major challenge to those caring for pregnant women with type 1 diabetes.Preconception care programs are associated with both reduced malformations and fewer early fetal losses in pregnant women with type 1 diabetes (12–14), perhaps due to improved glycemic control in the first stages of pregnancy. It is possible that working with women to improve metabolic control and optimize their insulin regimen before pregnancy might also help to reduce the high rate of severe episodes of hypoglycemia postconception, but this has yet to be demonstrated.We recently completed a randomized, open-label, parallel-group, multinational, multicenter study investigating maternal and fetal outcomes in 322 women with type 1 diabetes treated with either prandial insulin aspart (IAsp) or human insulin (15–17). IAsp injected immediately before eating was as effective and well tolerated as human insulin administered 30 min before eating. Although the study was somewhat underpowered, there were strong trends toward improved postprandial glucose control and prevention of severe hypoglycemia in the IAsp group (15,16). This study supports the conclusions of trials in nonpregnant individuals with type 1 diabetes, which suggest that the advantages of rapid-acting insulin analogs are most likely to be seen in those with tight control (18–20).The aim of this exploratory analysis was to compare the incidence of severe hypoglycemia during pregnancy between women enrolled into the trial either preconception or early in the first trimester. Finally, we also compared the effects of the different insulins on rates of severe hypoglycemia according to the time of enrollment of (pregnant) women into the study.     

Effects of diet soda on gut hormones in youths with diabetes

OBJECTIVE

In patients with type 2 diabetes, but not type 1 diabetes, abnormal secretion of incretins in response to oral nutrients has been described. In healthy youths, we recently reported accentuated glucagon-like peptide 1 (GLP-1) secretion in response to a diet soda sweetened with sucralose and acesulfame-K. In this study, we examined the effect of diet soda on gut hormones in youths with diabetes.

RESEARCH DESIGN AND METHODS

Subjects aged 12–25 years with type 1 diabetes (n = 9) or type 2 diabetes (n = 10), or healthy control participants (n = 25) drank 240 mL cola-flavored caffeine-free diet soda or carbonated water, followed by a 75-g glucose load, in a randomized, cross-over design. Glucose, C-peptide, GLP-1, glucose-dependent insulinotropic peptide (GIP), and peptide Tyr-Tyr (PYY) were measured for 180 min. Glucose and GLP-1 have previously been reported for the healthy control subjects.

RESULTS

GLP-1 area under the curve (AUC) was 43% higher after ingestion of diet soda versus carbonated water in individuals with type 1 diabetes (P = 0.020), similar to control subjects (34% higher, P = 0.029), but was unaffected by diet soda in patients with type 2 diabetes (P = 0.92). Glucose, C-peptide, GIP, and PYY AUC were not statistically different between the two conditions in any group.

CONCLUSIONS

Ingestion of diet soda before a glucose load augmented GLP-1 secretion in type 1 diabetic and control subjects but not type 2 diabetic subjects. GIP and PYY secretion were not affected by diet soda. The clinical significance of this increased GLP-1 secretion, and its absence in youths with type 2 diabetes, needs to be determined.Nonnutritive sweeteners are commonly consumed by both children and adults and have previously been thought to be metabolically inert. However, recent animal data demonstrate that nonnutritive sweeteners, including sucralose (Splenda) and acesulfame-K, play an active metabolic role within the gastrointestinal tract via sweet taste receptors identical to those found in lingual taste buds (1,2). In both humans and animals, these receptors are present in L cells of the gut mucosa secreting glucagon-like peptide 1 (GLP-1) and peptide Tyr-Tyr (PYY) (3–5). Components of the taste-signaling pathway have also been found in glucose-dependent insulinotropic peptide (GIP)-secreting K cells in the gut mucosa (5).GLP-1 and GIP are incretin hormones that increase glucose-dependent insulin secretion in response to oral nutrients. In healthy individuals, GIP appears to be responsible for the majority of the incretin effect (6,7). GLP-1 and its analogs have numerous physiologic effects, including delayed gastric emptying (8,9), increased satiety (10), and suppression of glucagon secretion (11), in addition to increased insulin secretion (12). Patients with type 2 diabetes frequently have normal GIP but impaired GLP-1 secretion (13) and are resistant to exogenous GIP but respond normally to exogenous GLP-1 (7). This has been exploited pharmacologically using GLP-1 analogs, which cause improved glycemia and weight loss. Both GLP-1 and GIP secretion are normal in type 1 diabetes (14). PYY acts as an anorectic hormone in both lean (15) and obese humans (16), although its secretion is attenuated in obesity (17).Sucralose has been shown to increase release of both GLP-1 and GIP in vitro in enteroendocrine cell lines (4,5). In vivo, however, the nonnutritive sweeteners sucralose (in humans and animals) and acesulfame, stevia, and d-tryptophan (in animals) do not stimulate GLP-1, GIP, or PYY secretion in the absence of caloric sugars (18,19). We recently demonstrated in a pilot study that diet soda (Diet Rite Cola, sweetened with sucralose and acesulfame-K) in the presence of glucose augmented glucose-stimulated GLP-1 secretion in healthy subjects (20). It is not known whether GIP or PYY secretion are likewise augmented by ingestion of nonnutritive sweeteners in addition to glucose or whether diet soda augments GLP-1 secretion in disease states such as type 1 or type 2 diabetes.In this study, we investigated whether subjects with diabetes (both type 1 and type 2) would demonstrate increased GLP-1 secretion after ingestion of diet soda in addition to a glucose load, similar to the effect previously observed in healthy subjects (20). In addition, we examined whether secretion of the gut hormones GIP and PYY is increased by ingestion of diet soda.     

Randomized Comparison of Pramlintide or Mealtime Insulin Added to Basal Insulin Treatment for Patients With Type 2 Diabetes

OBJECTIVE

To compare the efficacy and safety of adding mealtime pramlintide or rapid-acting insulin analogs (RAIAs) to basal insulin for patients with inadequately controlled type 2 diabetes.

RESEARCH DESIGN AND METHODS

In a 24-week open-label, multicenter study, 113 patients were randomly assigned 1:1 to addition of mealtime pramlintide (120 μg) or a titrated RAIA to basal insulin and prior oral antihyperglycemic drugs (OADs). At screening, patients were insulin naive or had been receiving <50 units/day basal insulin for <6 months. The basal insulin dosage was titrated from day 1, seeking fasting plasma glucose (FPG) ≥70–<100 mg/dl. Pramlintide and an RAIA were initiated on day 1 and week 4, respectively. The proportion of patients achieving A1C ≤7.0% without weight gain or severe hypoglycemia at week 24 was the primary end point.

RESULTS

More pramlintide- than RAIA-treated patients achieved the primary end point (30 vs. 11%, P = 0.018) with a similar dose of basal insulin. Pramlintide and an RAIA yielded similar mean ± SEM values for FPG and A1C at 24 weeks (122 ± 7 vs. 123 ± 5 mg/dl and 7.2 ± 0.2 vs. 7.0 ± 0.1%, respectively) and similar least squares mean reductions from baseline to end point (−31 ± 6 vs. −34 ± 6 mg/dl and −1.1 ± 0.2 vs. −1.3 ± 0.2%, respectively). RAIAs but not pramlintide caused weight gain (+4.7 ± 0.7 vs. +0.0 ± 0.7 kg, P < 0.0001). Fewer patients reported mild to moderate hypoglycemia with pramlintide than with the RAIA (55 vs. 82%), but more patients reported nausea (21 vs. 0%). No severe hypoglycemia occurred in either group.

CONCLUSIONS

In patients taking basal insulin and OADs, premeal fixed-dose pramlintide improved glycemic control as effectively as titrated RAIAs. The pramlintide regimen sometimes caused nausea but no weight gain and less hypoglycemia.Adding basal insulin therapy to oral agents improves glycemic control for many patients with type 2 diabetes, but up to 50% of patients continue to have A1C values >7% (1,2,3,4,5). Persistent after-meal hyperglycemia is generally observed in such patients (6). The usual next step in treatment is addition of mealtime insulin injections, but this approach increases risks of weight gain and hypoglycemia (4,6).Previous studies have shown that defects in addition to insulin deficiency contribute to after-meal hyperglycemia. Both insulin and amylin are secreted by β-cells, and, in individuals with abnormal β-cell function, glucose- and mixed meal–stimulated secretion of both hormones is delayed and reduced (7,8,9). Insulin deficiency impairs suppression of hepatic glucose production and enhancement of glucose uptake by tissues that normally limit postmeal hyperglycemia. Amylin deficiency accelerates gastric emptying, increases glucagon secretion, and alters satiety mechanisms (10,11).Pramlintide, an injectable synthetic analog of amylin, slows gastric emptying, attenuates postprandial glucagon secretion, enhances satiety, and reduces food intake (12,13,14). Pramlintide is approved as adjunctive treatment for patients with diabetes who use mealtime insulin with or without oral antihyperglycemic drugs (OADs) and have not achieved desired glucose control. Recently, a 16-week, double-blind, placebo-controlled study of patients with type 2 diabetes showed that pramlintide reduces A1C and weight without increasing insulin-induced hypoglycemia when added to basal insulin ± OADs without mealtime insulin (15).Pramlintide may offer an additional therapeutic option for mealtime use by patients with type 2 diabetes already using basal insulin. Rapid-acting insulin analogs (RAIAs) and pramlintide have different mechanisms of action and different patterns of desired and unwanted effects. Although both can limit after-meal hyperglycemia, RAIAs often cause weight gain and hypoglycemia (6), whereas pramlintide is associated with weight loss and nausea (15,16). This study was designed to compare the efficacy and side effects of pramlintide versus RAIAs when added to basal insulin to intensify treatment of type 2 diabetes.     

Physical Activity, Adiposity, and Diabetes Risk in Middle-Aged and Older Chinese Population: The Guangzhou Biobank Cohort Study

OBJECTIVE

Physical activity may modify the association of adiposity with type 2 diabetes. We investigated the independent and joint association of adiposity and physical activity with fasting plasma glucose, impaired fasting glucose, and type 2 diabetes in a Chinese population.

RESEARCH DESIGN AND METHODS

Middle-aged and older Chinese (n = 28,946, ≥50 years, 72.4%women) from the Guangzhou Biobank Cohort Study were examined in 2003–2008. Multivariable regression was used in a cross-sectional analysis.

RESULTS

BMI, waist circumference, and waist-to-hip ratio (WHR) were positively associated with type 2 diabetes after multiple adjustment, most strongly for WHR with odds ratio (OR) of 3.99 (95% CI 3.60–4.42) for highest compared with lowest tertile. Lack of moderate-to-vigorous physical activity, but not walking, was associated with diabetes with an OR of 1.29 (1.17–1.41). The association of moderate-to-vigorous activity with fasting glucose varied with WHR tertiles (P = 0.01 for interaction). Within the high WHR tertile, participants who had a lack of moderate-to-vigorous activity had an OR of 3.87 (3.22–4.65) for diabetes, whereas those who were active had an OR of 2.94 (2.41–3.59).

CONCLUSIONS

In this population, WHR was a better measure of adiposity-related diabetes risk than BMI or waist circumference. Higher moderate-to-vigorous activity was associated with lower diabetes risk, especially in abdominally obese individuals.Type 2 diabetes is a worldwide cause of morbidity and mortality. Adiposity, especially abdominal adiposity, seems to be at the core of development of hyperglycemia and type 2 diabetes (1). Increased physical activity may mitigate some of the diabetogenic impact of adiposity (2–4). Individuals who are obese but fit could even have a lower risk of mortality than those who are normal weight but unfit (5,6). However, being physically active does not completely abolish the obesity-related risk for cardiovascular disease and associated mortality (7). Adiposity is still the main risk factor for the development of type 2 diabetes (2–4,8). Although increased physical activity has been shown to be associated with reduced type 2 diabetes risk independent of adiposity, the protective effects may differ by the level of adiposity. However, the group that could benefit most from physical activity for the prevention of diabetes is still unclear (2–4,8–10).Understanding the relationship between adiposity and physical activity is important to stratify risk groups for the development of effective diabetes prevention strategies from public health and clinical perspectives. Most of the studies relate to Caucasians (2–4,8–10), whereas Asians, including Chinese and Indians, are possibly more vulnerable to insulin resistance (11). The number of Chinese adults with type 2 diabetes was estimated to be ∼28.1 million in 2000 and may double by 2030, with China being second only to India (12). The purpose of this study was to investigate the independent and joint association of adiposity and physical activity with fasting plasma glucose, impaired fasting glucose (IFG), and type 2 diabetes in 28,946 middle-aged and older Chinese participants in the Guangzhou Biobank Cohort Study.     

Cognitive Function Is Disrupted by Both Hypo- and Hyperglycemia in School-AgedChildren With Type 1 Diabetes: A Field Study

OBJECTIVE

We developed a field procedure using personal digital assistant (PDA) technology to test the hypothesis that naturally occurring episodes of hypo- and hyperglycemia are associated with deterioration in cognitive function in children with type 1 diabetes.

RESEARCH DESIGN AND METHODS

A total of 61 children aged 6–11 years with type 1 diabetes received a PDA programmed with two brief cognitive tests (mental math and choice reaction time), which they completed just before home glucose readings. The computer recorded time to complete each test and number of correct responses. Children completed several trials per day over 4–6 weeks for a total of 70 trials. Performance variables were compared across glucose ranges. Individual impairment scores (IISs) were also computed for each child by calculating the SD between performance during euglycemia and that during glucose extremes.

RESULTS

Time to complete both mental math and reaction time was significantly longer during hypoglycemia. During hyperglycemia, time to complete math was significantly longer and reaction time was marginally significant (P = 0.053). There were no differences on task accuracy. Decline in mental math performance was equivalent at glucose levels <3.0 and >22.2 mmol/l. IISs varied greatly across children, with no age or sex differences.

CONCLUSIONS

A decrease in mental efficiency occurs with naturally occurring hypo- and hyperglycemic glucose fluctuations in children with type 1 diabetes, and this effect can be detected with a field procedure using PDA technology. With blood glucose levels >22.2 mmol/l, cognitive deterioration equals that associated with significant hypoglycemia.In adults with type 1 diabetes, the negative impact of acute glucose extremes on cognitive and motor function is well documented. This is especially true for the disruptive effects of hypoglycemia, which have been demonstrated in numerous laboratory studies using insulin clamp techniques (1–5) and in field studies (6). More recently, there is growing evidence that acute hyperglycemia can also disrupt cognitive performance in adults with both type 1 and type 2 diabetes (6–8), although there are some discrepant findings (5). Evidence for cognitive deterioration has obvious clinical implications for people living withdiabetes, many of whom experiencehypo- and hyperglycemia on a relatively frequent basis. Such disruptions would also have clinical significance for children with type 1 diabetes; however, surprisingly few studies have examined these effects in pediatric populations. Only one published laboratory study (9) tested the impact of acute hypoglycemia in adolescents and found that even with relatively mild hypoglycemia (3.1–3.6 mmol/l), mental efficiency significantly decreased. Two laboratory studies have examined the impact of acute hyperglycemia in pediatric patients with mixed results, with one finding no effect in adolescents tested at 20 mmol/l (10) and the other finding a significant decline at glucose levels above 20 mmol/l (11).One major barrier to investigating the effects of acute hypo- and hyperglycemia on cognitive function in pediatric populations is reluctance to induce extreme glucose levels, and possible neurological insult, in younger patients with developing brains (12). However, glucose excursions more extreme than those induced in studies occur routinely outside of the laboratory in children with type 1 diabetes. Therefore, one way to bypass the ethical problems that arise in neurocognitive research involving pediatric patients is to develop experimental procedures that take advantage of these naturally occurring hypo- and hyperglycemic episodes. We have previously used personal digital assistant (PDA) technology to investigate the impact of daily hyperglycemia, including postprandial increases, on cognitive performance in adults with type 1 and type 2 diabetes (6,7). Patients performed brief cognitive tests on a PDA before home glucose measurements, repeating 50–70 trials over 1 month. A comparison of performance during hyperglycemia (>15 mmol/l) and euglycemia showed a significant decline at higher glucose levels. There was, however, large individual variability in the effects of hyperglycemia, with ∼50% of adults showing clinically significant disruption.The purpose of this study was to develop and test a similar computerized field procedure to assess cognitive performance at different glucose levels in school-aged youth with type 1 diabetes. This field procedure was then used to test the hypothesis that children experience significant disruptions in cognitive performance in their daily lives due to naturally occurring episodes of both acute hypo- and hyperglycemia. Children performed two brief cognitive tests on a PDA just before home glucose measurements three to five times per day over a period of ∼1 month, completing a total of 70 trials. After completing each test, children made subjective ratings of the difficulty of performing the task to determine the degree to which they were subjectively aware of changes in cognitive function. Individual impairment scores (IISs) were computed for each child to examine relationships between cognitive disruption and several demographic and clinical variables,including age, sex, diabetes duration, history of severe hypoglycemia, and metabolic control.     

Glucose metabolism in 105 children and adolescents after pancreatectomy for congenital hyperinsulinism

OBJECTIVE

To describe the long-term metabolic outcome of children with congenital hyperinsulinism after near-total or partial elective pancreatectomy.

RESEARCH DESIGN AND METHODS

Patients (n = 105: 58 diffuse and 47 focal congenital hyperinsulinism) received operations between 1984 and 2006. Follow-up consisted of periodic measurements of pre- and postprandial plasma glucose over 24 h, OGTT, and IVGTT. Cumulative incidence of hypo- or hyperglycemia/insulin treatment was estimated by Kaplan-Meier analysis.

RESULTS

After near-total pancreatectomy, 59% of children with diffuse congenital hyperinsulinism still presented mild or asymptomatic hypoglycemia that responded to medical treatments and disappeared within 5 years. One-third of the patients had both preprandial hypoglycemia and postprandial hyperglycemia. Hyperglycemia was found in 53% of the patients immediately after surgery; its incidence increased regularly to 100% at 13 years. The cumulative incidence of insulin-treated patients was 42% at 8 years and reached 91% at 14 years, but the progression to insulin dependence was very variable among the patients. Plasma insulin responses to IVGTT and OGTT correlated well with glycemic alterations. In focal congenital hyperinsulinism, hypoglycemia or hyperglycemia were rare, mild, and transient.

CONCLUSIONS

Patients with focal congenital hyperinsulinism are cured of hypoglycemia after limited surgery, while the outcome of diffuse congenital hyperinsulinism is very variable after near-total pancreatectomy. The incidence of insulin-dependent diabetes is very high in early adolescence.Congenital hyperinsulinism is the most common cause of persistent severe hypoglycemia at birth or in early infancy, requiring early intensive multidisciplinary management to prevent brain damage (1,2). The inappropriate secretion of insulin by the β-cells has heterogeneous genetic origins. In the neonatal forms of congenital hyperinsulinism, the most common genetic mutations (in ABCC8 and KCNJ11 genes) cause alterations of the ATP-dependent K⁺ channels (SUR1 and Kir6.2 subunits) in the β-cells, which play a critical role in the regulation of insulin secretion (3).The frequent resistance of congenital hyperinsulinism to medical treatments often leads to surgery, which has for a long time consisted of near-total pancreatectomy, with a high risk of insulin-dependent diabetes (4–7). However, the differentiation between two forms—the diffuse form with no histological anomalies but signs of β-cell hyperfunction and the adenomatous localized hyperplasia—has considerably changed the surgical treatment and the prognosis of the disease (8,9). The focal forms can indeed be definitively cured of hypoglycemia with partial elective pancreatectomy (10). The preoperative distinction between the two forms was initially established using selective pancreatic venous catherization (11,12), which has recently been abandoned for the less invasive positron emission tomography with [¹⁸F]fluoro-l-DOPA (13).The long-term outcome of patients suffering from congenital hyperinsulinism has not been well described (4,5,14–17). Few studies have clearly differentiated diffuse and focal forms of insulin hypersecretion. If the incidence of postoperative recurrent hypoglycemia was often documented, the follow-up was often short and data upon glucose tolerance and insulin secretion were rarely available, making it difficult to evaluate the incidence of postsurgical diabetes, although the risk seems to be high before the second decade of life after near-total pancreatectomy (4,5,16).We report the long-term follow-up study of glucose and insulin metabolism in 105 children who underwent surgery for either a focal or a diffuse form of congenital hyperinsulinism. The study clearly confirms the contrast between the evolution of the two forms but also shows the great variability in the incidence of hypoglycemia and hyperglycemia within the diffuse form and contributes to characterizing insulin secretion and sensitivity and to determining the investigations needed for an optimal follow-up.