Postprandial Vascular Effects of VIAject Compared With Insulin Lispro and Regular Human Insulin in Patients With Type 2 Diabetes

OBJECTIVE

Recent studies suggested an impact of prandial insulin delivery on postprandial regulation of tissue blood flow. This study compared the effect of VIAject with human regular insulin and insulin lispro on postprandial oxidative stress and endothelial function in patients with type 2 diabetes.

RESEARCH DESIGN AND METHODS

Fourteen patients (seven men; aged 61.5 ± 1.8 years; duration of diabetes 6.6 ± 4.6 years; A1C 7.2 ± 0.5% [mean ± SEM]) received a prandial injection of VIAject, human regular insulin, and insulin lispro. At baseline and after a standardized liquid meal test (Ensure Plus), the postprandial increases in asymmetric dimethylarginine (ADMA) and nitrotyrosine levels were investigated. In addition, the postprandial effects on microvascular blood flow, skin oxygenation, and vascular elasticity were measured.

RESULTS

Treatment with VIAject resulted in a significant reduction in the peak postprandial generation of ADMA compared with human insulin and insulin lispro (VIAject −27.3 ± 22.6, human insulin 97.7 ± 24.4, and insulin lispro 66.9 ± 33.9 nmol/l; P < 0.05, respectively). The postprandial increases in nitrotyrosine levels were significantly less after VIAject than after human regular insulin (VIAject −0.22 ± 0.17 vs. human insulin 0.25 ± 0.15 μg/ml; P < 0.05), whereas nitrotyrosine after insulin lispro was in between (insulin lispro 0.09 ± 0.07 μg/ml; NS). In parallel, earlier and more pronounced increases in microvascular blood flow and skin oxygenation were obtained after VIAject compared with those after human insulin or insulin lispro (P < 0.05, respectively). All insulin formulations resulted in comparable improvements in central arterial elasticity.

CONCLUSIONS

Treatment with VIAject reduced postprandial oxidative stress and improved endothelial function compared with human regular insulin or insulin lispro.Type 2 diabetes is closely related to atherosclerosis and the development of cardiovascular complications such as myocardial infarction or stroke. Recent studies on cardiovascular end points in patients with type 2 diabetes call into question the value of A1C-focused treatments in reducing macrovascular complications of diabetes (1–3). Other markers such as glucose excursions, hypoglycemia, or postprandial generation of oxidative stress may add important information for the judgment of cardiovascular risk in patients with type 2 diabetes (1,2). Postprandial microvascular blood flow is under dynamic regulation and is diversely affected by changes in postprandial glucose and insulin levels (4). Increasing postprandial insulin levels stimulate microvascular blood flow by inducing the endothelial release of nitric oxide via the activation of the phosphatidylinositol 3-kinase system (5,6). In contrast, increasing blood glucose levels were shown to oppose the insulin effects on endothelial cells and to impair postprandial microvascular blood flow (7). A reduced first-phase insulin release with an augmented increase in postprandial glucose levels followed by an impairment in endothelial function and postprandial microvascular blood flow is an early feature of type 2 diabetes (4,8). These findings suggest that a physiological timing of prandial insulin release fulfills an important role not only in controlling postprandial blood glucose levels but also in maintaining normal tissue perfusion and nutrition. In addition, recent studies have shown that in insulin-treated patients with type 1 and type 2 diabetes, the pharmacokinetic profile of insulin formulations affects postprandial microvascular blood flow and that treatment with fast-acting insulin analogs reduces postprandial oxidative stress and restores endothelial function more effectively than treatment with human regular insulin (9–11).VIAject is a new, ultra–fast-acting insulin formulation shown to have more rapid insulin absorption than that for human regular insulin and insulin lispro. The aim of this study was to compare the effect of preprandial subcutaneous administration of insulin VIAject with preprandial application of human regular insulin and insulin lispro on several markers of endothelial and microvascular function after a standardized liquid meal test in patients with type 2 diabetes.     

Closed-Loop Insulin Delivery Using a Subcutaneous Glucose Sensor and Intraperitoneal Insulin Delivery: Feasibility study testing a new model for the artificial pancreas

OBJECTIVE

Attempts to build an artificial pancreas by using subcutaneous insulin delivery from a portable pump guided by an subcutaneous glucose sensor have encountered delays and variability of insulin absorption. We tested closed-loop intraperitoneal insulin infusion from an implanted pump driven by an subcutaneous glucose sensor via a proportional-integral-derivative (PID) algorithm.

RESEARCH DESIGN AND METHODS

Two-day closed-loop therapy (except for a 15-min premeal manual bolus) was compared with a 1-day control phase with intraperitoneal open-loop insulin delivery, according to randomized order, in a hospital setting in eight type 1 diabetic patients treated by implanted pumps. The percentage of time spent with blood glucose in the 4.4–6.6 mmol/l range was the primary end point.

RESULTS

During the closed-loop phases, the mean ± SEM percentage of time spent with blood glucose in the 4.4–6.6 mmol/l range was significantly higher (39.1 ± 4.5 vs. 27.7 ± 6.2%, P = 0.05), and overall dispersion of blood glucose values was reduced among patients. Better closed-loop glucose control came from the time periods excluding the two early postprandial hours with a higher percentage of time in the 4.4–6.6 mmol/l range (46.3 ± 5.3 vs. 28.6 ± 7.4, P = 0.025) and lower mean blood glucose levels (6.9 ± 0.3 vs. 7.9 ± 0.6 mmol/l, P = 0.036). Time spent with blood glucose <3.3 mmol/l was low and similar for both investigational phases.

CONCLUSIONS

Our results demonstrate the feasibility of intraperitoneal insulin delivery for an artificial β-cell and support the need for further study. Moreover, according to a semiautomated mode, the features of the premeal bolus in terms of timing and amount warrant further research.In patients with type 1 diabetes, the near-normal glucose control required to prevent long-term complications (1,2) remains difficult to achieve (3). Indeed, the incidence of hypoglycemia increases when glucose control approaches normal glucose levels (4). For this reason the development of an “artificial pancreas” has been a goal for >30 years (5,6).An artificial β-cell requires three elements: a continuous insulin delivery device, a continuous glucose monitoring system, and a control algorithm linking insulin delivery to glucose measurements (3,7,8). The recent development of better performing continuous glucose sensors renewed the potential feasibility of closed-loop insulin delivery (9–11). Short-term initiatives in the clinical research setting were reported in recent years but showed some limitations (12–14). Key limiting factors were, first, delays in the modulation of insulin action related to subcutaneous infusion and, second, time lags in glucose detection due to either the placement of the sensors in the interstitial compartment of subcutaneous tissue or the internal structure of implanted intravenous sensors (15). To reduce glucose deviations at mealtimes, a hybrid option of closed-loop insulin delivery includes a manual priming bolus (16).Reported benefits of intraperitoneal insulin infusion from implantable pumps include fast insulin action and low basal plasma insulin levels, resulting in tight glucose control and a low incidence of hypoglycemic events (17). The feasibility of automated closed-loop insulin delivery from implantable pumps has been demonstrated in clinical trials performed with the Long-Term Sensor System, which coupled these devices with an intravenous glucose sensor (18).Our approach to optimize closed-loop glucose control includes the use of closer to physiological intraperitoneal insulin delivery, subcutaneous glucose sensing, and a proportional-integral-derivative (PID) algorithm with a manual premeal bolus, resulting in a hybrid PID (HyPID) system. The objective of this study was to test the feasibility of such an approach. We investigated patients in the same controlled hospital setting while testing the HyPID system and when following their usual self-management. This approach marks a difference from the previously reported closed-loop trials, which considered home-use periods for comparison with in-clinic closed-loop studies (13,16).     

Further Improvement in Postprandial Glucose Control With Addition of Exenatide or Sitagliptin to Combination Therapy With Insulin Glargine and Metformin: A proof-of-concept study

OBJECTIVE

To assess the effect of a 4-week adjunctive therapy of exenatide (EXE) (5–10 μg b.i.d.) or sitagliptin (SITA) (100 mg once daily) in response to a standardized breakfast meal challenge in 48 men or women with type 2 diabetes receiving insulin glargine (GLAR) + metformin (MET).

RESEARCH DESIGN AND METHODS

This was a single-center, randomized, open-label, active comparator–controlled study with a three-arm parallel group design, consisting of: screening, 4- to 8-week run-in period, 4-week treatment period, and follow-up. In all three groups, the GLAR dose was titrated according to an algorithm (fasting blood glucose ≤100 mg/dl).

RESULTS

The unadjusted 6-h postprandial blood glucose excursion of both GLAR + MET + EXE and GLAR + MET + SITA was statistically significantly smaller than that of GLAR + MET (606 ± 104 vs. 612 ± 133 vs. 728 ± 132 mg/dl/h; P = 0.0036 and 0.0008). A1C significantly decreased in all three groups (P < 0.0001), with the greatest reduction of −1.9 ± 0.7 under GLAR + MET + EXE (GLAR + MET + SITA −1.5 ± 0.7; GLAR + MET −1.2 ± 0.5%-points; GLAR + MET + EXE vs. GLAR + MET P = 0.0154). The American Diabetes Association A1C target of <7.0% was reached by 80.0, 87.5, and 62.5% of subjects, respectively. GLAR + MET + EXE had the highest number (47) of adverse events, mostly gastrointestinal (56%) with one dropout. GLAR + MET or GLAR + MET + SITA only had 10 and 12 adverse events, respectively, and no dropouts. Hypoglycemia (blood glucose <50 mg/dl) rates were low and comparable among groups. Weight decreased with GLAR + MET + EXE (−0.9 ± 1.7 kg; P = 0.0396) and increased slightly with GLAR + MET (0.4 ± 1.5 kg; NS; GLAR + MET + EXE vs. GLAR + MET P = 0.0377).

CONCLUSIONS

EXE or SITA added to GLAR + MET further substantially reduced postprandial blood glucose excursions. Longer-term studies in a larger population are warranted to confirm these findings.The UK Prospective Diabetes Study (UKPDS) demonstrated that good glycemic control in type 2 diabetes is associated with a reduced risk of diabetes complications (1). After lifestyle modifications (diet and exercise) and oral hypoglycemic agents (OHAs) the addition of basal insulin to OHAs is common practice (2), because this kind of regimen requires only a single injection in most cases and can improve glycemic control. Its use, however, may not adequately control postprandial hyperglycemia or may be associated with hypoglycemia and/or weight gain (3,4). Because obesity is frequently present in subjects with type 2 diabetes (5) and represents a factor contributing to insulin resistance (5) and cardiovascular risk (5), weight gain may be particularly undesirable.A significant advance in basal insulin therapy was the introduction of insulin glargine, a long-acting insulin analog with an extended duration of action of ∼24 h without exhibiting a pronounced peak (6,7). In subjects with type 2 diabetes, insulin glargine was shown to confer glycemic control at least equivalent to that of NHP insulin with a lower incidence of hypoglycemia (3,8,9). However, insulin glargine still has the drawbacks of insulin treatment such as weight gain (3,8,9) and a lower effect on postprandial glucose excursions (8) than on fasting glucose values.Exenatide is the first-in-class glucagon-like peptide 1 (GLP-1) receptor agonist (or incretin mimetic) approved in the U.S. and Europe (10). Compared with placebo, exenatide statistically reduced A1C, whereas there was no difference in A1C improvement between exenatide and insulin glargine or biphasic insulin aspart (11–14). However, postprandial glycemia as well as weight was further reduced with exenatide compared with insulin glargine or biphasic insulin, with a similar risk of hypoglycemia (12,13).Sitagliptin is an approved once-daily, potent, and highly selective dipeptidyl peptidase-4 (DPP-4) inhibitor (15). When added to metformin, sitagliptin, given at a dose of 100 mg once daily over 24 weeks, led to significant reductions in A1C, fasting, and 2-h postprandial plasma glucose and was weight-neutral (16).With this background, a therapy controlling both fasting blood glucose (FBG) and postprandial glucose excursions seems to be a promising approach for subjects with type 2 diabetes (17–21). Therefore, in the present study we investigated the influence of a 4-week adjunctive therapy of either a GLP-1 receptor agonist (exenatide) or a DPP-4 inhibitor (sitagliptin) to titrated basal insulin (insulin glargine) plus metformin versus the continuation with titrated insulin glargine plus metformin alone as active comparator in subjects with type 2 diabetes.     

��-Cell�CMediated Signaling Predominates Over Direct ��-Cell Signaling in the Regulation of Glucagon Secretion in Humans

OBJECTIVE

Given evidence of both indirect and direct signaling, we tested the hypothesis that increased β-cell–mediated signaling of α-cells negates direct α-cell signaling in the regulation of glucagon secretion in humans.

RESEARCH DESIGN AND METHODS

We measured plasma glucagon concentrations before and after ingestion of a formula mixed meal and, on a separate occasion, ingestion of the sulfonylurea glimepiride in 24 basal insulin-infused, demonstrably β-cell–deficient patients with type 1 diabetes and 20 nondiabetic, demonstrably β-cell–sufficient individuals; the latter were infused with glucose to prevent hypoglycemia after glimepiride.

RESULTS

After the mixed meal, plasma glucagon concentrations increased from 22 ± 1 pmol/l (78 ± 4 pg/ml) to 30 ± 2 pmol/l (103 ± 7 pg/ml) in the patients with type 1 diabetes but were unchanged from 27 ± 1 pmol/l (93 ± 3 pg/ml) to 26 ± 1 pmol/l (89 ± 3 pg/ml) in the nondiabetic individuals (P < 0.0001). After glimepiride, plasma glucagon concentrations increased from 24 ± 1 pmol/l (83 ± 4 pg/ml) to 26 ± 1 pmol/l (91 ± 4 pg/ml) in the patients with type 1 diabetes and decreased from 28 ± 1 pmol/l (97 ± 5 pg/ml) to 24 ± 1 pmol/l (82 ± 4 pg/ml) in the nondiabetic individuals (P < 0.0001). Thus, in the presence of both β-cell and α-cell secretory stimuli (increased amino acid and glucose levels, a sulfonylurea) glucagon secretion was prevented when β-cell secretion was sufficient but not when β-cell secretion was deficient.

CONCLUSIONS

These data indicate that, among the array of signals, indirect reciprocal β-cell–mediated signaling predominates over direct α-cell signaling in the regulation of glucagon secretion in humans.The regulation of pancreatic islet α-cell glucagon secretion is complex (1–10). It involves direct signaling of α-cells (1) and indirect signaling of α-cells by β-cell (2–6) and δ-cell (7) secretory products, the autonomic nervous system (8,9), and gut incretins (10).Appropriate glucagon secretory responses occur from the perfused pancreas (3,5) and perifused islets (2). Low plasma glucose concentrations stimulate glucagon secretion from the transplanted (i.e., denervated) human pancreas (11) and the denervated dog pancreas (12). Therefore, we have focused on the intraislet regulation of glucagon secretion. Furthermore, because selective destruction of β-cells results in loss of the glucagon response to hypoglycemia in type 1 diabetes (13), and partial reduction of the β-cell mass in minipigs results in impaired postprandial suppression of glucagon secretion (14), we have focused on the role of β-cell–mediated signaling in the regulation of glucagon secretion.Findings from studies of the perfused rat (3,4) and human (5) pancreas, rats in vivo (6), rat islets (2), isolated rat α-cells (2), and humans (15–18) have been interpreted to indicate that a β-cell secretory product or products tonically restrains basal α-cell glucagon secretion during euglycemia and that a decrease in β-cell secretion, coupled with low glucose concentrations at the α-cells, signals an increase in glucagon secretion in response to hypoglycemia. Parenthetically, the relative roles of the candidate β-cell secretory products (insulin, zinc, γ-aminobutyric acid, and amylin, among others) (2) that normally restrain α-cell glucagon secretion remain to be determined. However, that interpretation rests, in part, on results of studies in isolated rat α-cells (2), which are debated (1), and on the evidence that the islet microcirculation flows from β-cells to α-cells to δ-cells (4), which is also debated (19). Furthermore, it does not address the plausible possibility that a decrease in intraislet δ-cell somatostatin secretion might also signal an increase in α-cell glucagon secretion during hypoglycemia (7).Given that interpretation, it follows that an increase in β-cell secretion would signal a decrease in glucagon secretion in the postprandial state (14). The concept is an interplay of indirect reciprocal β-cell–mediated signaling of α-cells and of direct α-cell signaling in the regulation of glucagon secretion.There is, in our view, compelling evidence that, among other mechanisms, both indirect reciprocal β-cell–mediated signaling of α-cells (2–6) and direct α-cell signaling (1) are involved in the regulation of glucagon secretion by nutrients, hormones, neurotransmitters, and drugs. Given that premise, we posed the question: Which of these predominates in humans? Accordingly, we tested the hypothesis that increased β-cell–mediated signaling of α-cells negates direct α-cell signaling in the regulation of glucagon secretion in humans. To do so, we measured plasma glucagon responses to ingestion of a mixed meal and, on a separate occasion, to ingestion of the sulfonylurea glimepiride in patients with type 1 diabetes and in nondiabetic individuals. We conceptualized patients with type 1 diabetes as a model of α-cells isolated from β-cells because their β-cells had been destroyed but they have functioning α-cells. (Their α-cells are not, of course, isolated from other islet cells, including δ-cells.) Increased plasma amino acid and glucose levels after a mixed meal and sulfonylureas normally stimulate β-cell secretion; increased plasma amino acid and perhaps glucose (2) levels after a mixed meal and sulfonylureas (1) stimulate α-cell secretion. Our hypothesis predicts that such factors that normally stimulate both β-cells and α-cells would stimulate glucagon secretion in patients with type 1 diabetes but not in nondiabetic individuals, i.e., in the virtual absence and the presence of β-cell function, respectively. Indeed, a mixed meal (20,21) and the secretagogues tolbutamide (22), glyburide (23), and repaglinide (23) have been reported to raise plasma glucagon concentrations in patients with type 1 diabetes, but all of those studies lacked nondiabetic control subjects.     

Obesity Blunts Microvascular Recruitment in Human Forearm Muscle After a Mixed Meal

OBJECTIVE

Ingestion of a mixed meal recruits flow to muscle capillaries and increases total forearm blood flow in healthy young lean people. We examined whether these vascular responses are blunted by obesity.

RESEARCH DESIGN AND METHODS

We fed eight middle-aged lean and eight obese overnight-fasted volunteers a liquid mixed meal (480 kcal). Plasma glucose and insulin were measured every 30 min, and brachial artery flow and muscle microvascular recruitment (contrast ultrasound) were assessed every 60 min over 2 h after the meal.

RESULTS

By 30 min, plasma glucose rose in both the lean (5.1 ± 0.1 vs. 6.7 ± 0.4 mmol/l, P < 0.05) and the obese groups (5.4 ± 0.2 vs. 6.7 ± 0.4 mmol/l, P < 0.05). Plasma insulin rose (28 ± 4 vs. 241 ± 30 pmol/l, P < 0.05) by 30 min in the lean group and remained elevated for 2 h. The obese group had higher fasting plasma insulin levels (65 ± 8 pmol/l, P < 0.001) and a greater postmeal area under the insulin-time curve (P < 0.05). Brachial artery flow was increased at 120 min after the meal in the lean group (38 ± 6 vs. 83 ± 16 ml/min, P < 0.05) but not in the obese group. Muscle microvascular blood volume rose by 120 min in the lean group (14.4 ± 2.2 vs. 24.4 ± 4.2 units, P < 0.05) but not in the obese group.

CONCLUSIONS

A mixed meal recruits muscle microvasculature in lean subjects, and this effect is blunted by obesity. This impaired vascular recruitment lessens the endothelial surface available and may thereby impair postprandial glucose disposal.Skeletal muscle is a major site for insulin-mediated glucose storage and thereby influences postprandial plasma glucose levels (1). Over the past 15 years it has become increasingly evident that insulin exerts important actions on muscle vasculature as an integral part of its action to increase glucose disposal (2–5). Within muscle the vascular endothelium is the first tissue that insulin encounters. A primary function of the endothelium is to serve as a permeability barrier that restricts transport of macromolecules such as insulin into the interstitial space. In addition to modulating delivery of insulin to muscle cells, the endothelium also directly responds to insulin by increasing production of nitric oxide, a potent vasodilator, and endothelin-1, a potent vasoconstrictor, to regulate muscle blood flow (6,7).Baron and colleagues (2,8,9) hypothesized that insulin increases leg blood flow to facilitate access of glucose and insulin to muscle, thereby increasing glucose disposal. Blocking insulin-induced increases in blood flow reduced insulin-stimulated glucose disposal by ∼30%. Furthermore, this vascular action of insulin was significantly blunted in insulin-resistant obese humans (8).These investigators used a thermodilution method that measured only total limb blood flow and not microvascular responses. Others have measured the effect of insulin on limb blood flow using a variety of methods with divergent findings (10,11). Our laboratories have developed new methods that assess the microvascular action of insulin in muscle (3,5,12,13). We reasoned that microvascular perfusion directly mediates nutrient exchange in muscle (14). We have previously shown that insulin acts on preterminal arterioles (which control microvascular blood flow) more rapidly and at more physiologically relevant insulin concentrations than is the case for resistance arteries (which control total muscle blood flow) (3,5,12).Using contrast-enhanced ultrasound (CEU) and the euglycemic insulin clamp method, we observed that physiological hyperinsulinemia expands the volume of microvasculature perfused in forearm muscle of healthy lean people (4,15) and that this action of insulin is markedly impaired in obese subjects (4). Indeed, we observed a negative correlation between insulin-mediated microvascular recruitment in muscle and BMI (4). Although the clamp technique provides an excellent assessment of the physiological actions of insulin, it does not mimic the changes that typically occur after the ingestion of a mixed meal. With the meal there are changes in blood glucose, amino acids, gut hormones, and parasympathetic/sympathetic tone. Few studies have reported on the effect of a meal on total limb blood flow, and these have yielded conflicting results. Although some investigators reported that the ingestion of a mixed meal (16) or an oral glucose load (17) increased total limb blood flow, others reported no effect (18). These differences may relate to techniques used to measure flow, the types of meals ingested, and differences in the population studied. However, in each of these clinical studies, investigators have measured only total limb blood flow and not microvascular responses.We have recently reported that ingestion of a mixed meal by lean young adults increases total forearm blood flow and increases microvascular flow (19). These vascular responses occurred at a time when plasma insulin was significantly elevated. Whether total muscle blood flow along with muscle microvascular recruitment after the ingestion of a mixed meal is normal or blunted in insulin-resistant obese subjects is unknown, and addressing this issue was the goal of the current study. We used Doppler ultrasound to study total forearm blood flow and CEU to quantify muscle microvascular responses of forearm muscle in healthy lean and otherwise healthy obese age-matched adults in response to a mixed meal. We hypothesized that both total limb blood flow and the microvascular response would be blunted by obesity.     

Insulin Response in Relation to Insulin Sensitivity: An appropriate ��-cell response in black South African women

OBJECTIVE

The purpose of this study was to characterize differences in the acute insulin response to glucose (AIR_g) relative to insulin sensitivity (S_I) in black and white premenopausal normoglycemic South African women matched for body fatness.

RESEARCH DESIGN AND METHODS

Cross-sectional analysis including 57 black and white South African women matched for BMI, S_I, AIR_g, and the disposition index (AIR_g × S_I) were performed using a frequently sampled intravenous glucose tolerance test with minimal model analysis, and similar measures were analyzed using an oral glucose tolerance test (OGTT). Body composition was assessed by dual-energy X-ray absorptiometry and computed tomography.

RESULTS

S_I was significantly lower (4.4 ± 0.8 vs. 9.4 ± 0.8 and 2.9 ± 0.8 vs. 6.0 ± 0. 8 × 10⁻⁵ min⁻¹/[pmol/l], P < 0.001) and AIR_g was significantly higher (1,028 ± 255 vs. 352 ± 246 and 1,968 ± 229 vs. 469 ± 246 pmol/l, P < 0.001), despite similar body fatness (30.9 ± 1.4 vs. 29.7 ± 1.3 and 46.8 ± 1.2 vs. 44.4 ± 1.3%) in the normal-weight and obese black women compared with their white counterparts, respectively. Disposition index, a marker of β-cell function, was not different between ethnic groups (3,811 ± 538 vs. 2,966 ± 518 and 3,646 ± 485 vs. 2,353 ± 518 × 10⁻⁵ min, P = 0.10). Similar results were obtained for the OGTT-derived measures.

CONCLUSIONS

Black South African women are more insulin resistant than their white counterparts but compensate by increasing their insulin response to maintain normal glucose levels, suggesting an appropriate β-cell response for the level of insulin sensitivity.Type 2 diabetes is a significant contributor to morbidity and mortality worldwide and was ranked as the seventh leading cause of death among individuals of all ages in South Africa in 2000 (1). The relatively high prevalence of diabetes has been accompanied by a high prevalence of obesity in South-African women (2), as 87% of all type 2 diabetes in South Africa has been attributed to excess body weight (3).For reasons that have not yet been explained, both black South African and African American women are more insulin resistant than their adiposity-matched Caucasian counterparts (4–8). Insulin resistance in African Americans has been associated with hyperinsulinemia (6–8), due in part to reduced hepatic insulin extraction (7,8). In contrast, insulin resistance in black South African women has been associated with insulinopenia (5,9,10). However, the women in the previous studies were either not matched for glucose tolerance (5,10) or glucose tolerance and insulin sensitivity were not measured (9), making interpretation of β-cell function difficult. Thus, it is an open question whether β-cell function, assessed using state-of-the-art methods, differs in normoglycemic South African women of different ethnicities who are otherwise well matched.It has become clear that insulin sensitivity is an important modulator of the β-cell response (11). The relationship between insulin sensitivity and insulin response is hyperbolic in nature, such that as insulin sensitivity decreases, normal β-cells will increase their insulin response to maintain normoglycemia. This hyperbolic relationship allows for the product of insulin sensitivity and insulin response to be calculated, with the resultant parameter being termed the disposition index. The disposition index is highly heritable and correlates strongly with glucose tolerance such that individuals with the lowest disposition index are at increased risk for or already have type 2 diabetes (12).By estimating the disposition index, we aimed to better define β-cell function in black and white South African women matched for body fatness. Further, we aimed to compare these measures with estimates of glucose metabolism obtained using an oral glucose tolerance test (OGTT).     

Mixing Insulin Aspart With Detemir Does Not Affect Glucose Excursion in Children With Type 1 Diabetes

OBJECTIVE

We hypothesized that insulin detemir mixed with aspart had equivalent effects on blood glucose as if being given as separate injections in pediatric type 1 diabetes patients.

RESEARCH DESIGN AND METHODS

Fourteen children with type 1 diabetes were randomly assigned to either Study A (mixed insulins) or Study B (separate insulins) for the first 10 days and crossed over for the last 10 days. Each subject underwent continuous glucose monitoring on the last 72 h of each study.

RESULTS

The 48-h area under the curve (mmol/hour/l), M-value, and mean amplitude of glucose excursion (mmol/l) for Study A versus Study B were 457 ± 70 versus 469 ± 112 (P = 0.58), 39.67 ± 15.37 versus 39.75 ± 9.69 (P = 0.98), and 6.35 ± 1.92 versus 5.98 ± 0.92 (P = 0.42), respectively.

CONCLUSIONS

Insulin detemir mixed with aspart had equivalent effects on blood glucose versus giving them as separate injections in children with type 1 diabetes.One of the barriers to good glycemic control in children with type 1 diabetes is multiple daily insulin injections (1,2). Mixing rapid-acting and slow-acting insulins in the same syringe would decrease the number of injections and may improve adherence (3,4). Although there are concerns that mixing the insulins would change the glucose excursion (5), mixing rapid-acting insulin (aspart or lispro) with slow-acting insulin glargine in the same syringe immediately before use did not change the glucose excursion and rates of hypoglycemia (3,4). We hypothesized that slow-acting insulin detemir mixed with aspart would have equivalent effects on blood glucose versus giving them as separate injections in children with type 1 diabetes.     

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.     

Glycemia and Its Relationship to Outcomes in the Metformin in Gestational Diabetes Trial

OBJECTIVE

To determine how glucose control in women with GDM treated with metformin and/or insulin influenced pregnancy outcomes.

RESEARCH DESIGN AND METHODS

Women randomly assigned to metformin or insulin treatment in the Metformin in Gestational Diabetes (MiG) trial had baseline glucose tolerance test (OGTT) results and A1C documented, together with all capillary glucose measurements during treatment. In the 724 women who had glucose data for analysis, tertiles of baseline glucose values and A1C and of mean capillary glucose values during treatment were calculated. The relationships between maternal factors, glucose values, and outcomes (including a composite of neonatal complications, preeclampsia, and large-for-gestational-age [LGA] and small-for-gestational-age infants) were examined with bivariable and multivariate models.

RESULTS

Baseline OGTT did not predict outcomes, but A1C predicted LGA infants (P = 0.003). During treatment, fasting capillary glucose predicted neonatal complications (P < 0.001) and postprandial glucose predicted preeclampsia (P = 0.016) and LGA infants (P = 0.001). Obesity did not influence outcomes, and there was no interaction between glycemic control, randomized treatment, or maternal BMI in predicting outcomes. The lowest risk of complications was seen when fasting capillary glucose was <4.9 mmol/l (mean ± SD 4.6 ± 0.3 mmol/l) compared with 4.9–5.3 mmol/l or higher and when 2-h postprandial glucose was 5.9–6.4 mmol/l (6.2 ± 0.2 mmol/l) or lower.

CONCLUSIONS

Glucose control in women with gestational diabetes mellitus treated with metformin and/or insulin is strongly related to outcomes. Obesity is not related to outcomes in this group. Targets for fasting and postprandial capillary glucose may need to be lower than currently recommended.Although treatment of gestational diabetes mellitus (GDM) has been shown to improve perinatal outcomes (1,2), there is lack of consensus about ideal glucose targets and how other factors, such as fetal abdominal circumference, should influence these targets (3,4). The Fifth International Workshop-Conference on Gestational Diabetes endorsed targets of capillary fasting glucose <5.3 mmol/l, 1-h postprandial <7.8 mmol/l, and/or 2-h postprandial <6.7 mmol/l until further data addressing optimal goals become available (5). Improved pregnancy outcomes have been reported in women achieving these targets compared with those in women who did not (6); the latter group had higher baseline mean BMI and A1C, which may have influenced outcomes. Obesity has been reported as an independent factor influencing outcome in women with GDM treated with diet but not in those treated with insulin (7,8).Published studies have compared women who aim for or achieve predetermined glucose targets with those who do not: it is not clear whether such aims are optimal and whether glycemia influences different outcomes equally. Several studies suggested that treatment intensity can be usefully stratified according to fetal abdominal circumference measured by ultrasound (3): intensive treatment of women carrying fetuses with an abdominal circumference above the 70–75th percentile lowered the frequency of large-for-gestational-age (LGA) infants without increasing rates of small-for-gestational-age (SGA) infants. However, lowering of mean maternal glucose to <4.8 mmol/l is associated with increased frequency of SGA infants (9).Data showing relationships between different fasting and postprandial glucose values and a range of outcomes would assist clinicians in setting target ranges for “optimal glucose control” more objectively. In the Metformin in Gestational Diabetes (MiG) trial, women with GDM, who had one or more home capillary blood glucose measures ≥5.5 mmol/l fasting or ≥6.7 mmol/l 2-h postprandial after lifestyle intervention, were randomly assigned to either insulin or metformin treatment (10). The primary objective of the trial was to compare metformin with insulin treatment, but prespecified secondary objectives were to determine the impact of glycemia on outcomes and to determine whether treatment with metformin or insulin was more effective at different levels of glycemia. Baseline glycemia measures and capillary glucose measures throughout treatment were recorded in the trial database. The specific aims of the present analysis were 1) to determine how glucose control influenced trial outcomes, including the primary outcome (a composite of neonatal complications), maternal preeclampsia, and rates of LGA and SGA infants; 2) to identify additional baseline factors influencing outcomes, including baseline glycemia and obesity; and 3) to examine any differences between treatment arms at different levels of glycemia.     

Utilizing the second-meal effect in type 2 diabetes: practical use of a soya-yogurt snack

OBJECTIVE

To evaluate the effect of a prebreakfast high-protein snack upon postbreakfast hyperglycemia.

RESEARCH DESIGN AND METHODS

We studied 10 men and women with diet- and/or metformin-controlled type 2 diabetes. Metabolic changes after breakfast were compared between 2 days: breakfast taken only and soya-yogurt snack taken prior to breakfast.

RESULTS

There was a significant lower rise in plasma glucose on the snack day. The incremental area under the glucose curve was 450 ± 55 mmol · min/l on the snack day compared with 699 ± 99 mmol · min/l on the control day (P = 0.013). The concentration of plasma free fatty acids immediately before breakfast correlated with the increment in plasma glucose (r = 0.50, P = 0.013).

CONCLUSIONS

Consuming a high-protein prebreakfast snack results in almost 40% reduction of postprandial glucose increment. The second-meal effect can be applied simply and practically to improve postbreakfast hyperglycemia in people with type 2 diabetes.Previous studies (1,2) have shown a considerable reduction in hyperglycemia after the second meal of the day, provided that breakfast had been taken. The preservation of this effect in type 2 diabetes was not confirmed until recently (3). Postprandial hyperglycemia acts as an independent risk factor for cardiovascular disease (4–6), a major cause of death in subjects with type 2 diabetes (7).We hypothesized that postbreakfast hyperglycemia in subjects with type 2 diabetes could be improved nonpharmacologically by using a high-protein, low-carbohydrate prebreakfast snack.     

Acute Effects of Decaffeinated Coffee and the Major Coffee Components Chlorogenic Acid and Trigonelline on Glucose Tolerance

OBJECTIVE

Coffee consumption has been associated with lower risk of type 2 diabetes. We evaluated the acute effects of decaffeinated coffee and the major coffee components chlorogenic acid and trigonelline on glucose tolerance.

RESEARCH DESIGN AND METHODS

We conducted a randomized crossover trial of the effects of 12 g decaffeinated coffee, 1 g chlorogenic acid, 500 mg trigonelline, and placebo (1 g mannitol) on glucose and insulin concentrations during a 2-h oral glucose tolerance test (OGTT) in 15 overweight men.

RESULTS

Chlorogenic acid and trigonelline ingestion significantly reduced glucose (−0.7 mmol/l, P = 0.007, and −0.5 mmol/l, P = 0.024, respectively) and insulin (−73 pmol/l, P = 0.038, and −117 pmol/l, P = 0.007) concentrations 15 min following an OGTT compared with placebo. None of the treatments affected insulin or glucose area under the curve values during the OGTT compared with placebo.

CONCLUSIONS

Chlorogenic acid and trigonelline reduced early glucose and insulin responses during an OGTT.In prospective cohort studies, higher coffee consumption has been associated with a lower risk of type 2 diabetes (1,2). Associations have been similar for caffeinated and decaffeinated coffee (1,3–5), suggesting that coffee components other than caffeine have beneficial effects on glucose homeostasis. Coffee is a major source of the phenolic compound chlorogenic acid (6) and the vitamin B3 precursor trigonelline (7), which have been shown to reduce blood glucose concentrations in animal studies (5–8). This is the first study to investigate the acute effects of chlorogenic acid and trigonelline on glucose tolerance in humans.     

The Importance of Caloric Restriction in the Early Improvements in Insulin Sensitivity After Roux-en-Y Gastric Bypass Surgery

OBJECTIVE

Many of the metabolic benefits of Roux-en-Y gastric bypass (RYGB) occur before weight loss. In this study we investigated the influence of caloric restriction on the improvements in the metabolic responses that occur within the 1st week after RYGB.

RESEARCH METHODS AND DESIGN

A mixed meal was administered to nine subjects before and after RYGB (average 4 ± 0.5 days) and to nine matched, obese subjects before and after 4 days of the post-RYGB diet.

RESULTS

Weight loss in both groups was minimal; the RYGB subjects lost 1.4 ± 5.3 kg (P = 0.46) vs. 2.2 ± 1.0 kg (P = 0.004) in the calorically restricted group. Insulin resistance (homeostasis model assessment of insulin resistance) improved with both RYGB (5.0 ± 3.1 to 3.3 ± 2.1; P = 0.03) and caloric restriction (4.8 ± 4.1 to 3.6 ± 4.1; P = 0.004). The insulin response to a mixed meal was blunted in both the RYGB and caloric restriction groups (113 ± 67 to 65 ± 33 and 85 ± 59 to 65 ± 56 nmol · l⁻¹ · min⁻¹, respectively; P < 0.05) without a change in the glucose response. Glucagon-like peptide 1 levels increased (9.2 ± 8.6 to 12.2 ± 5.5 pg · l⁻¹ · min⁻¹; P = 0.04) and peaked higher (45.2 ± 37.3 to 84.8 ± 33.0 pg/ml; P = 0.01) in response to a mixed meal after RYGB, but incretin responses were not altered after caloric restriction.

CONCLUSIONS

These data suggest that an improvement in insulin resistance in the 1st week after RYGB is primarily due to caloric restriction, and the enhanced incretin response after RYGB does not improve postprandial glucose homeostasis during this time.Bariatric surgical procedures achieve a large and sustained improvement in insulin sensitivity and a high resolution rate in type 2 diabetes. The metabolic benefits of Roux-en-Y gastric bypass surgery (RYGB) are observed very early and precede substantial weight loss (1). It has been proposed that the long-term improvements are related to a reduction in fat mass (2); however, the mechanisms for the early improvements remain uncertain. The surgical bypass of the foregut and/or rapid nutrient exposure of the distal gut alters enterokine release, which has been proposed to result in metabolic improvements (3) and in particular glucose homeostasis. However, caloric restriction in the absence of weight loss has metabolic benefits (4) and could also contribute to the early improvements in glucose homeostasis.The incretins, namely glucagon-like peptide 1 (GLP-1) and gastric inhibitory peptide (GIP), are gut hormones that contribute to postprandial insulin secretion (5). RYGB augments GLP-1 secretion, whereas its impact on GIP is less consistent (3). In contrast, bariatric procedures that induce weight loss by caloric restriction in the absence of intestinal bypass, such as adjustable gastric banding, do not alter postprandial incretin levels (3). Ghrelin is another enterokine that has a primary role in appetite stimulation but also has glucose and insulin modulatory effects (6). The presence of an acyl group is considered necessary for biological activity of ghrelin, although the desacyl form probably has biological functions as well (7). Ghrelin levels are abnormally low in obese individuals and remain suppressed after RYGB, whereas weight loss by diet enhances ghrelin levels (8). Leptin and adiponectin, adipocyte-derived hormones, are thought to be mediators of weight-related improvements in insulin resistance. The concentrations of these hormones are aberrant in obesity and normalize after RYGB. A recent study indicated that >5% weight loss by consumption of a hypocaloric diet (∼40% energy restriction) is required to favorably change circulating adipokines and metabolic parameters (9).A limited number of reports have directly compared the contribution of duodenal bypass versus caloric restriction on enterokine responses and hormone levels after RYGB (10–12). These studies all incorporated moderate weight loss (∼10 kg) and were conducted 2–4 weeks postoperatively. In the present study, we compared the immediate, weight loss–independent effects of RYGB and caloric restriction on fasting hormone levels and meal-stimulated enterokine release. RYGB were evaluated within the 1st week after surgery, and a matched group of subjects were evaluated after 4 days of the equivalent post–bariatric surgery diet.     

Oral Insulin: A Comparison With Subcutaneous Regular Human Insulin in Patients With Type 2 Diabetes

OBJECTIVE

To determine the pharmacokinetic and pharmacodynamic properties of an oral insulin (OI) formulation compared with subcutaneously injected regular human insulin (RHI).

RESEARCH DESIGN AND METHODS

Ten male patients with type 2 diabetes (means ± SD; A1C 7.0 ± 1.1%; BMI 28.3 ± 2.7 kg/m²) received either 300 units of insulin combined with 400 mg of delivery agent orally or 15 units RHI subcutaneously under isoglycemic clamp conditions.

RESULTS

Maximum insulin concentration was greater and onset of action was faster with OI (C_max 93 ± 71 vs. 33 ± 11 μU/ml; AUC_GIR^(0−1h) 173 ± 86 vs. 27 ± 32 mg/kg; P < 0.05). Mean insulin concentration and glucose infusion rate returned to baseline within 3 h after OI administration. Relative bioavailability of OI was 7 ± 4% (1st 2 h).

CONCLUSIONS

This proof-of-concept study demonstrated that absorption of OI is feasible under fasting conditions. OI has a fast onset and a short duration of action but also shows a rather high between-subject variability in absorption.Oral administration of insulin has the potential advantage of a more physiological action by its direct effect on hepatic glucose production (1,2). Thus far various oral insulin approaches however have only partially produced satisfactory results (1,3,4). Gastrointestinal absorption of insulin is hampered by factors such as enzymatic degradation and lack of permeation through epithelial cells (5). Noncovalent interaction of the novel drug-carrier molecule monosodium N-(4-chlorosalicyloyl)-4-aminobutyrate (4-CNAB) with insulin might create more favorable physico-chemical properties for gastrointestinal insulin absorption (6,7). In this study, 4-CNAB has been combined with human insulin to facilitate gastrointestinal insulin absorption.     

Determinants of Impaired Fasting Glucose Versus Glucose Intolerance in Polycystic Ovary Syndrome

OBJECTIVE

To determine insulin resistance and response in patients with polycystic ovary syndrome (PCOS) and normal glucose tolerance (NGT), impaired fasting glucose (IFG), impaired glucose tolerance, and combined glucose intolerance (CGI).

RESEARCH DESIGN AND METHODS

In this cross-sectional study, 143 patients with PCOS (diagnosed on the basis of National Institutes of Health criteria) underwent oral glucose tolerance testing (OGTT), and 68 patients also had frequently sampled intravenous glucose tolerance tests. Changes in plasma glucose, insulin, cardiovascular risk factors, and androgens were measured.

RESULTS

Compared with patients with NGT, those with both IFG and CGI were significantly insulin resistant (homeostasis model assessment 3.3 ± 0.2 vs. 6.1 ± 0.9 and 6.4 ± 0.5, P < 0.0001) and hyperinsulinemic (insulin area under the curve for 120 min 973 ± 69 vs. 1,470 ± 197 and 1,461 ± 172 pmol/l, P < 0.0001). Insulin response was delayed in patients with CGI but not in those with IFG (2-h OGTT, insulin 1,001 ± 40 vs. 583 ± 45 pmol/l, P < 0.0001). Compared with the NGT group, the CGI group had a lower disposition index (1,615 ± 236 vs. 987 ± 296, P < 0.0234) and adiponectin level (11.1 ± 1.1 vs. 6.2 ± 0.8 ng/ml, P < 0.0096). Compared with the insulin-resistant tertile of the NGT group, those with IFG had a reduced insulinogenic index (421 ± 130 vs. 268 ± 68, P < 0.05). Compared with the insulin-sensitive tertile of the NGT group, the resistant tertile had higher triglyceride and high-sensitivity C-reactive protein (hs-CRP) and lower HDL cholesterol and sex hormone–binding globulin (SHBG). In the entire population, insulin resistance correlated directly with triglyceride, hs-CRP, and the free androgen index and inversely with SHBG.

CONCLUSIONS

Patients with PCOS develop IFG and CGI despite having significant hyperinsulinemia. Patients with IFG and CGI exhibit similar insulin resistance but very different insulin response patterns. Increases in cardiac risk factors and free androgen level precede overt glucose intolerance.Women with polycystic ovary syndrome (PCOS) are at risk for impaired glucose tolerance (IGT), type 2 diabetes, and gestational diabetes mellitus (1) owing to abnormalities in insulin secretion and action (2–4). The specific defect is increased serine and decreased tyrosine phosphorylation of the insulin receptor (5). Patients who develop glucose intolerance have a relative decrease in insulin secretion as well (4). Women with PCOS are hyperinsulinemic compared with weight-matched control subjects (1). Hyperinsulinemia worsens and insulin sensitizers improve ovarian dysfunction and hyperandrogenemia in PCOS (6). Therefore, assessing glucose homeostasis by an oral glucose tolerance test (OGTT) has become a common practice.Definition and interpretation of glucose intolerance have changed in recent years. The fasting glucose cutoff for diabetes was reduced from 140 to 126 mg/dl and the new term, impaired fasting glucose (IFG), was introduced for the values between 110 and 125 mg/dl (7). In 2003, the cutoff value for normal fasting glucose was reduced to 100 mg/dl (8). In addition, recent research demonstrated that the pathophysiology of isolated IFG differs from that of isolated IGT (defined by glucose levels >140 mg/dl at 2 h of an OGTT). The former results from hepatic insulin resistance, whereas the latter results from peripheral insulin resistance (9,10). Those individuals who exhibit combined glucose intolerance (CGI) have resistance at both sites. In addition, cardiovascular risk factors are more commonly encountered with glucose intolerance (IGT and CGI) than with isolated IFG (11).Although glucose intolerance is found in one-third of patients with PCOS, so far only one study investigated the insulin resistance and secretion in patients with PCOS with IFG or IGT/CGI (12). Our study was undertaken to determine the differences in insulin secretion and action in patients with PCOS exhibiting different types of glucose intolerance.     

Effect of diacerein on insulin secretion and metabolic control in drug-naive patients with type 2 diabetes: a randomized clinical trial

OBJECTIVE

To assess the effect of diacerein on insulin secretion and metabolic control in drug-naïve patients with type 2 diabetes.

RESEARCH DESIGN AND METHODS

A randomized, double-blind, placebo-controlled clinical trial was carried out in 40 drug-naïve adult patients with type 2 diabetes. A metabolic profile including interleukin (IL)-1β, tumor necrosis factor-α, IL-6, and fasting insulin levels was carried out before the intervention and 2 months afterward. A hyperglycemic-hyperinsulinemic clamp technique was performed to assess the phases of insulin secretion and insulin sensitivity. After randomization, 20 patients received diacerein (50 mg once daily) for the first 15 days and twice daily for 45 additional days. The remaining patients received placebo. Intra- and intergroup differences were calculated by Wilcoxon signed rank and Mann-Whitney U tests.

RESULTS

There were significant increases in first (102 ± 63 vs. 130 ± 75 pmol/L; P < 0.01), late (219 ± 111 vs. 280 ± 135 pmol/L; P < 0.01), and total insulin (178 ± 91 vs. 216 ± 99 pmol/L; P < 0.01) secretions without changes in insulin sensitivity after diacerein administration. There were significant decreases in fasting glucose (7.9 ± 1.4 vs. 6.8 ± 1.0 mmol/L; P < 0.01) and in A1C levels (8.3 ± 1.0 vs. 7.0 ± 0.8%; P < 0.001) after diacerein administration. There were no significant changes after placebo administration in the above-mentioned evaluations.

CONCLUSIONS

Insulin secretion increased and metabolic control improved after diacerein administration in drug-naïve patients with type 2 diabetes.It has been suggested that several epigenetic factors are involved in the pathogenesis of type 2 diabetes; however, its development is at least partially a direct consequence of obesity (1,2). Obesity is associated with a low-grade chronic inflammatory state, which to a large extent emanates from adipose tissue. With its secretion of bioactive molecules, this may have an effect on insulin sensitivity in the liver and peripheral tissues as well as on insulin secretion, with a negative impact on the cardiovascular system (3,4). Some cytokines, in particular, tumor necrosis factor-α (TNF-α) and interleukin (IL)-1β, are involved in apoptosis of β-cells, decreasing insulin secretion with the consequent hyperglycemia (4,5).Diacerein is a medication used frequently in the treatment of some articular diseases as a result of its effect on the inflammatory process (6,7). Diacerein decreases cytokine concentrations, in particular, TNF-α and IL-1β, with an unknown mechanism of action (7,8). Therefore, if diacerein is prescribed for obese patients with type 2 diabetes, it may decrease cytokines, increase insulin secretion and probably insulin action, and thereby improve glucose control.The aim of this study was to assess the effect of diacerein on insulin secretion and metabolic control in drug-naïve patients with type 2 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.     

Phosphodiesterase 5 Inhibition Improves ��-Cell Function in Metabolic Syndrome

OBJECTIVE

This study tested the hypothesis that phosphodiesterase 5 inhibition alone or in combination with ACE inhibition improves glucose homeostasis and fibrinolysis in individuals with metabolic syndrome.

RESEARCH DESIGN AND METHODS

Insulin sensitivity, β-cell function, and fibrinolytic parameters were measured in 18 adults with metabolic syndrome on 4 separate days after a randomized, crossover, double-blind, 3-week treatment with placebo, ramipril (10 mg/day), tadalafil (10 mg o.d.), and ramipril plus tadalafil.

RESULTS

Ramipril decreased systolic and diastolic blood pressure, ACE activity, and angiotensin II and increased plasma renin activity. Ramipril did not affect insulin sensitivity or β-cell function. In contrast, tadalafil improved β-cell function (P = 0.01). This effect was observed in women (331.9 ± 209.3 vs. 154.4 ± 48.0 32 μ · mmol⁻¹ · l⁻¹, respectively, for tadalafil treatment vs. placebo; P = 0.01) but not in men. There was no effect of any treatment on fibrinolysis.

CONCLUSIONS

Phosphodiesterase 5 inhibition may represent a novel strategy for improving β-cell function in metabolic syndrome.Metabolic syndrome affects over 20% of U.S. adults, predicts diabetes, and will soon overtake smoking as the premier cardiovascular risk factor (1). Progression to type 2 diabetes results from impaired insulin sensitivity and pancreatic β-cell dysfunction (2,3). ACE inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) may decrease diabetes in high-risk individuals (4). These agents can improve insulin sensitivity by preventing inhibitory effects of angiotensin II on GLUT4 translocation (5) or improve insulin secretion by preventing angiotensin II type 1 receptor–dependent inhibition of insulin release (6).Nitric oxide (NO) may also contribute to salutary effects of ACEIs and ARBs on glucose homeostasis (7). NO stimulates muscle glucose uptake through cyclic guanosine monophosphate (cGMP) (7). In mice, inhibiting cGMP degradation by phosphodiesterase 5 increases insulin sensitivity and muscle glucose uptake (8). cGMP decreases apoptosis and increases intracellular calcium in pancreatic β-cells, suggesting an insulinotropic effect (9,10). We tested the hypothesis that decreasing degradation of cGMP would enhance any effect of ACE inhibition on insulin sensitivity or β-cell function in humans.     

Lipotoxicity and Decreased Islet Graft Survival

OBJECTIVE

To evaluate if baseline serum lipids are associated with islet graft survival in type 1 diabetes islet transplant (ITx) recipients.

RESEARCH DESIGN AND METHODS

Baseline fasting lipid profile was collected from 44 ITx recipients. Comparisons were performed between subjects below and above the median values of each lipid fraction. Differences in outcomes were compared by Kaplan-Meier curves and Cox regression analysis.

RESULTS

Subjects with baseline fasting plasma triglycerides and VLDL cholesterol above the median had shorter islet graft survival (triglycerides: 39.7 ± 6.1 vs. 61.3 ± 6.6 months, P = 0.029, and VLDL: 41.5 ± 5.7 vs. 62.8 ± 7.3 months, P = 0.032). Total, LDL, and HDL cholesterol did not influence islet function. Triglycerides (odds ratio 2.97 [95% CI 1.03–8.52], P = 0.044) maintained its association with graft failure after adjustments for confounders.

CONCLUSIONS

Higher baseline triglycerides are associated with earlier decline in islet graft function. Prospective clinical trials should address whether it is directly caused by lipotoxicity and if strategies focusing on lowering serum lipids may prolong islet graft survival.Increased free fatty acids (FFAs) cause β-cell dysfunction and death (1–3). β-Cell lipid accumulation is mediated by defective intracellular lipid oxidation associated with leptin resistance (4). This abnormality can be corrected by insulin sensitizers or leptin therapy (5,6). In addition, FFA-induced endoplasmic reticulum stress has been implicated in β-cell apoptosis (7), which could be minimized by glucagon-like peptide-1 agonists (8). Islet grafts infused directly into the liver receive lipid-rich postprandial blood. Insulin secreted by islet grafts promote triglyceride deposition in surrounding hepatocytes, and multifocal steatosis has been reported in ∼20% of islet transplant (ITx) recipients (9,10). Moreover, an insulin resistance phenotype and tendency for higher serum triglycerides, factors associated with steatosis (11), were predictors of shorter graft survival (12). The aim of this study was to determine whether the lipid profile of type 1 diabetic ITx recipients is associated with islet graft survival.     

Effects of Exenatide Alone and in Combination With Daclizumab on ��-Cell Function in Long-Standing Type 1 Diabetes

OBJECTIVE

In patients with long-standing type 1 diabetes, we investigated whether improved β-cell function can be achieved by combining intensive insulin therapy with agents that may 1) promote β-cell growth and/or limit β-cell apoptosis and 2) weaken the anti–β-cell autoimmunity.

RESEARCH DESIGN AND METHODS

For this study, 20 individuals (mean age 39.5 ± 11.1 years) with long-standing type 1 diabetes (21.3 ± 10.7 years) were enrolled in this prospective open-label crossover trial. After achieving optimal blood glucose control, 16 subjects were randomized to exenatide with or without daclizumab. Endogenous insulin production was determined by repeatedly measuring serum C-peptide.

RESULTS

In 85% of individuals with long-standing type 1 diabetes who were screened for participation in this trial, C-peptide levels ≥0.05 ng/ml (0.02 nmol/l) were found. Residual β-cells responded to physiological (mixed-meal) and pharmacological (arginine) stimuli. During exenatide treatment, patients lost 4.1 ± 2.9 kg body wt and insulin requirements declined significantly (total daily dose on exenatide 0.48 ± 0.11 vs. 0.55 ± 0.13 units · kg⁻¹ · day⁻¹ without exenatide; P = 0.0062). No signs of further activation of the underlying autoimmune disease were observed. Exenatide delayed gastric emptying, suppressed endogenous incretin levels, but did not increase C-peptide secretion.

CONCLUSIONS

In long-standing type 1 diabetes, which remains an active autoimmune disease even decades after its onset, surviving β-cells secrete insulin in a physiologically regulated manner. However, the combination of intensified insulin therapy, exenatide, and daclizumab did not induce improved function of these remaining β-cells.In the past 2 decades, several lines of research dominated the field of type 1 diabetes: trials to alter the immunological response against β-cells and attempts to develop and replace β-cells. The latter, represented by islet transplantation in the clinical arena, has led to the realization that lasting insulin independence could not be achieved (1), but progress was made by gaining insight into β-cell development (2–4) and immunomodulation. Experimental therapies such as administration of the monoclonal antibody anti-CD3 and the β-cell antigen GAD65 slowed β-cell destruction when administered soon after disease onset (5,6). Currently, however, no therapy is available that results in a complete halt or reversal of β-cell failure.We initiated this trial in patients with well-controlled long-standing type 1 diabetes who had evidence of endogenous insulin production documented by measurable C-peptide concentrations ≥0.3 ng/ml (0.1 nmol/l). The study participants received exenatide, a glucagon-like peptide (GLP)-1 agonist, to stimulate β-cell recovery and possibly regeneration (7,8); 50% of patients also received daclizumab to diminish the underlying autoimmunity and to curb a potential autoimmune reactivation. β-Cell function was repeatedly assessed by measuring basal and stimulated C-peptide concentrations (9). We speculated that the difference between greater β-cell mass and improved function could be determined by observing the duration of any treatment effect; i.e., if the intervention resulted in increased β-cell mass, improved pancreatic insulin production would be expected to persist beyond the exenatide treatment. Daclizumab was chosen as a mild immunosuppressive agent because of its safety profile and its demonstrated efficacy in other T-cell–mediated autoimmune conditions such as uveitis and multiple sclerosis (10,11).     

Early Glucose Abnormalities in Cystic Fibrosis Are Preceded by Poor Weight Gain

OBJECTIVE

Progressive β-cell loss causes catabolism in cystic fibrosis. Existing diagnostic criteria for diabetes were based on microvascular complications rather than on cystic fibrosis–specific outcomes. We aimed to relate glycemic status in cystic fibrosis to weight and lung function changes.

RESEARCH DESIGN AND METHODS

We determined peak blood glucose (BG_max) during oral glucose tolerance tests (OGTTs) with samples every 30 min for 33 consecutive children (aged 10.2–18 years). Twenty-five also agreed to undergo continuous glucose monitoring (CGM) (Medtronic). Outcome measures were change in weight standard deviation score (wtSDS), percent forced expiratory volume in 1 s (%FEV1), and percent forced vital capacity (%FVC) in the year preceding the OGTT.

RESULTS

Declining wtSDS and %FVC were associated with higher BG_max (both P = 0.02) and with CGM time >7.8 mmol/l (P = 0.006 and P = 0.02, respectively) but not with BG_{120 min}. A decline in %FEV1 was related to CGM time >7.8 mmol/l (P = 0.02). Using receiver operating characteristic (ROC) analysis to determine optimal glycemic cutoffs, CGM time above 7.8 mmol/l ≥4.5% detected declining wtSDS with 89% sensitivity and 86% specificity (area under the ROC curve 0.89, P = 0.003). BG_max ≥8.2 mmol/l gave 87% sensitivity and 70% specificity (0.76, P = 0.02). BG_{120 min} did not detect declining wtSDS (0.59, P = 0.41). After exclusion of two patients with BG_{120 min} ≥11.1 mmol/l, the decline in wtSDS was worse if BG_max was ≥8.2 mmol/l (−0.3 ± 0.4 vs. 0.0 ± 0.4 for BG_max <8.2 mmol/l, P = 0.04) or if CGM time above 7.8 mmol/l was ≥4.5% (−0.3 ± 0.4 vs. 0.1 ± 0.2 for time <4.5%, P = 0.01).

CONCLUSIONS

BG_max ≥8.2 mmol/l on an OGTT and CGM time above 7.8 mmol/l ≥4.5% are associated with declining wtSDS and lung function in the preceding 12 months.Progressive β-cell loss causes catabolism and weight loss in cystic fibrosis (1,2). Weight is a prognostic indicator (3), and prevention of weight decline is a major clinical objective in children and adolescents with cystic fibrosis. Median life expectancy of patients with cystic fibrosis has risen progressively over recent decades but remains drastically shorter (∼36 years) than that of the general population (4). The presence of cystic fibrosis–related diabetes (CFRD) is associated with an increase in early mortality of up to sixfold (5). CFRD is usually diagnosed by the North American Cystic Fibrosis Foundation criteria (6) or World Health Organization (WHO) criteria for diabetes (7). These criteria were designed to identify patients at risk of microvascular complications in type 2 diabetes (8) and were not designed with cystic fibrosis–specific outcomes in mind. Microvascular complications occur in cystic fibrosis (9); however, catabolic decline in weight and deteriorating lung function may be more relevant outcomes. Poor weight gain is associated with worsening lung function (10,11), and both are associated with early mortality (12,13). Weight and lung function declines have been shown to precede the diagnosis of CFRD by standard criteria (2), but the earliest glycemic abnormality associated with clinical decline has not been determined. Glycemic status can be assessed in detail using an oral glucose tolerance test (OGTT) with 30-min samples and, more recently, continuous interstitial fluid glucose monitoring (CGM). We aimed to determine the relationship between glycemic status and the change in weight standard deviation score (wtSDS) and the change in lung function over the preceding year.