Insulin resistance and hyperinsulinemia: is hyperinsulinemia the cart or the horse?

Insulin resistance, recently recognized as a strong predictor of disease in adults, has become the leading element of the metabolic syndrome and renewed as a focus of research. The condition exists when insulin levels are higher than expected relative to the level of glucose. Thus, insulin resistance is by definition tethered to hyperinsulinemia. The rising prevalence of medical conditions where insulin resistance is common has energized research into the causes. Many causes and consequences have been identified, but the direct contributions of insulin itself in causing or sustaining insulin resistance have received little sustained attention. We examine situations where insulin itself appears to be a proximate and important quantitative contributor to insulin resistance. 1) Mice transfected with extra copies of the insulin gene produce basal and stimulated insulin levels that are two to four times elevated. The mice are of normal weight but show insulin resistance, hyperglycemia, and hypertriglyceridemia. 2) Somogyi described patients with unusually high doses of insulin and hyperglycemia. Episodes of hypoglycemia with release of glucose-raising hormones, postulated as the culprits in early studies, have largely been excluded by studies including continuous glucose monitoring. 3) Rats and humans treated with escalating doses of insulin show both hyperinsulinemia and insulin resistance. 4) The pulsatile administration of insulin (rather than continuous) results in reduced requirements for insulin. 5) Many patients with insulinoma who have elevated basal levels of insulin have reduced (but not absent) responsiveness to administered insulin. In summary, hyperinsulinemia is often both a result and a driver of insulin resistance.     

Insulin: a wonder drug in the critically ill?

Stress hyperglycaemia is a common event in acute critical illness. There is increasing evidence that maintaining normoglycaemia and treatment with insulin (or with glucose–insulin–potassium [GIK]), even in non-diabetic persons, is helpful in limiting organ damage after myocardial infarction, stroke, traumatic brain injury and other conditions, even though the conditions may be accompanied by insulin resistance. A landmark study now suggests that maintaining normoglycaemia with intensive insulin treatment in a heterogeneous population of critically ill patients decreases morbidity and mortality. The potential mechanisms that underlie such a beneficial effect are discussed.     

Is a Priming Dose of Insulin Necessary in a Low-Dose Insulin Protocol for the Treatment of Diabetic Ketoacidosis?

OBJECTIVE—The purpose of this study was to assess the efficacy of an insulin priming dose with a continuous insulin infusion versus two continuous infusions without a priming dose.RESEARCH DESIGN AND METHODS—This prospective randomized protocol used three insulin therapy methods: 1) load group using a priming dose of 0.07 units of regular insulin per kg body weight followed by a dose of 0.07 unit · kg⁻¹ · h⁻¹ i.v. in 12 patients with diabetic ketoacidosis (DKA); 2) no load group using an infusion of regular insulin of 0.07 unit · kg body weight⁻¹ · h⁻¹ without a loading dose in 12 patients with DKA, and 3) twice no load group using an infusion of regular insulin of 0.14 · kg⁻¹ · h⁻¹ without a loading dose in 13 patients with DKA. Outcome was based on the effects of insulin therapy on biochemical and hormonal changes during treatment and recovery of DKA.RESULTS—The load group reached a peak in free insulin value (460 μU/ml) within 5 min and plateaued at 88 μU/ml in 60 min. The twice no load group reached a peak (200 μU/ml) at 45 min. The no load group reached a peak (60 μU/ml) in 60–120 min. Five patients in the no load group required supplemental insulin doses to decrease initial glucose levels by 10%; patients in the twice no load and load groups did not. Except for these differences, times to reach glucose ≤250 mg/dl, pH ≥7.3, and HCO₃⁻ ≥15 mEq/l did not differ significantly among the three groups.CONCLUSIONS—A priming dose in low-dose insulin therapy in patients with DKA is unnecessary if an adequate dose of regular insulin of 0.14 unit · kg body weight⁻¹ · h⁻¹ (about 10 units/h in a 70-kg patient) is given.Although positive therapeutic responses to low-dose insulin therapy have been established in adult patients with diabetic ketoacidosis (DKA) (1–8), none of these studies and guidelines for the treatment of DKA, including the American Diabetes Association (ADA) Consensus and Position Statements, has ever assessed or addressed the use of a continuous insulin infusion without a loading dose of insulin (9). In the current study, we used a dose of 0.14 unit · kg⁻¹ · h⁻¹ without a loading dose instead of the recommended 0.1 unit · kg⁻¹ · h⁻¹ with a loading dose. This insulin regimen was chosen because one study in a pediatric population used a dosing regimen of 0.1 unit · kg⁻¹ · h⁻¹ without a loading dose that resulted in a total plasma insulin level of 50–60 μU/ml (10). This level proved to be too low for optimal suppression of hepatic glucose output and optimal glucose uptake (11). In addition, bolus doses of insulin may result in hypokalemia as well as other undesirable effects (12), especially when used in a routine hospital setting.The efficacy of low-dose insulin without a priming dose has not been established in a prospective randomized study (13). Thus, the following questions have remained unanswered in the treatment of DKA: 1) Is an insulin bolus needed before a continuous insulin infusion? 2) What is the optimal insulin infusion rate if a bolus dose is not used? and 3) What is the dose response of continuous insulin infusion used alone in regard to decremental changes in glucose, metabolic parameters, cortisol, and free fatty acids (FFAs)? Therefore, we evaluated responses to three low-dose insulin regimens in 37 consecutive patients with DKA in a prospective randomized fashion to address these issues. Changes in plasma free insulin, serum potassium levels, and outcome recovery measures were assessed using a higher infusion dose (0.14 unit · kg⁻¹ · h⁻¹ without a bolus dose) compared with a lower infusion dose (0.07 unit · kg⁻¹ · h⁻¹) with and without a loading dose (0.07 unit/kg) of insulin.     

Insulin demand regulates β cell number via the unfolded protein response

Although stem cell populations mediate regeneration of rapid turnover tissues, such as skin, blood, and gut, a stem cell reservoir has not been identified for some slower turnover tissues, such as the pancreatic islet. Despite lacking identifiable stem cells, murine pancreatic β cell number expands in response to an increase in insulin demand. Lineage tracing shows that new β cells are generated from proliferation of mature, differentiated β cells; however, the mechanism by which these mature cells sense systemic insulin demand and initiate a proliferative response remains unknown. Here, we identified the β cell unfolded protein response (UPR), which senses insulin production, as a regulator of β cell proliferation. Using genetic and physiologic models, we determined that among the population of β cells, those with an active UPR are more likely to proliferate. Moreover, subthreshold endoplasmic reticulum stress (ER stress) drove insulin demand–induced β cell proliferation, through activation of ATF6. We also confirmed that the UPR regulates proliferation of human β cells, suggesting that therapeutic UPR modulation has potential to expand β cell mass in people at risk for diabetes. Together, this work defines a stem cell–independent model of tissue homeostasis, in which differentiated secretory cells use the UPR sensor to adapt organ size to meet demand.     

Making Insulin Accessible: Does Inhaled Insulin Fill an Unmet Need?

Glycemic control is fundamental to the management of diabetes. However, studies suggest that a significant proportion of people with diabetes, particularly those using insulin, are not achieving glycemic targets. The reasons for this are likely to be multifactorial. The real and perceived risk of hypoglycemia and the need for multiple daily injections are widely recognized as key barriers to effective insulin therapy. Therefore, there is a clear unmet need for a treatment option which can help mitigate these barriers. Alternative methods of insulin administration have been under investigation for several years, and pulmonary delivery has shown the most promise to date. Inhaled Technosphere^® Insulin (TI; Afrezza^®; MannKind Corporation) was approved in 2014 for use as prandial insulin in people with diabetes. TI shows a more rapid onset of action and a significantly faster decline in activity than current subcutaneous rapid-acting insulin analogs (RAAs), and TI is more synchronized to the physiologic timing of the postprandial glucose excursion. This results in lower postprandial hypoglycemia with similar glycemic control compared with RAAs, and less weight gain. Together with the ease of use of the TI inhaler and the reduction in the number of daily injections, these findings imply that TI may be useful in helping to overcome patient resistance to insulin, improve adherence and mitigate clinical inertia in health-care providers, with potential beneficial effects on glycemic control. Funding: Writing and editorial support in the preparation of this publication was funded by Sanofi US, Inc., Bridgewater, New Jersey, USA. Funding for the article processing charges for this publication was provided by MannKind Corporation.     

Insulin resistance and obstructive sleep apnea: is increased sympathetic stimulation the link?

The science of sleep is in early stages of development, and the biochemical consequences of obstructive sleep apnea (OSA) are slowly being identified. Only recently have investigators begun to identify the commonalities and interaction between OSA and insulin resistance, the underlying pathology of type 2 diabetes. Obesity and increasing age play important parts in the natural history of both conditions, which frequently coexist. The purpose of this article is, first, to examine the extent and strength of studies that have investigated the association between OSA and increased insulin resistance or type 2 diabetes and, second, to propose a model that explains the association and cyclical interaction between OSA, obesity, and insulin resistance.     

Inhaled Insulin: A Breath of Fresh Air? A Review of Inhaled Insulin

Purpose

Despite many advances in diabetes care over the last century, some elements of insulin therapy remain inadequate for optimal care of the patient with diabetes. There is a need for improved pharmacokinetics and pharmacodynamics of rapid-acting insulin analogues to mimic physiologic insulin secretion. In addition, a major barrier to successful insulin therapy has been patient resistance. Alternative routes of insulin administration, including inhaled insulin, have been under investigation for several years. This review discusses the rationale for pulmonary delivery of insulin, compares previous inhaled insulin products, reviews the literature on the safety and efficacy of a current inhaled insulin formulation under investigation, and compares this product with other prandial insulin products.

Methods

English-language studies and reviews of inhaled insulin were searched in MEDLINE, the ClinicalTrials.gov registry (through May 2014), and the US Food and Drug Administration Website.

Findings

Inhaled insulin has several favorable characteristics due to pulmonary anatomy/physiology and the lack of injections. Pharmacokinetic and pharmacodynamic studies have shown a time–action profile suitable for prandial insulin use. Inhaled insulin seems to be safe and effective compared with other prandial insulin products and may be preferable to subcutaneous rapid-acting insulin analogues in terms of time–action profiles and rates of hypoglycemia. Small decreases in forced expiratory volume in 1 second (FEV1) have been shown with inhaled insulin, although this finding is not progressive over time and reverses with cessation of the medication.

Implications

Although several inhaled insulin products have been under investigation, only one (Exubera^® [Nektar Therapeutics, San Carlos, California/Pfizer Inc, New York, New York]) was approved by the US Food and Drug Administration, and it was pulled from the market after only a short period of time. Technosphere^® insulin (MannKind Corporation, Valencia, California) is currently the only inhaled insulin that remains under investigation. A review of the past and present literature on inhaled insulin is pertinent in understanding the current status of inhaled insulin and its risks and benefits. The current literature suggests that inhaled insulin could be a valuable option for prandial insulin administration, with a favorable risk to benefit ratio in some patients.     

Measuring β-Cell Function Relative to Insulin Sensitivity in Youth: Does the hyperglycemic clamp suffice?

OBJECTIVE

To compare β-cell function relative to insulin sensitivity, disposition index (DI), calculated from two clamps (2cDI, insulin sensitivity from the hyperinsulinemic-euglycemic clamp and first-phase insulin from the hyperglycemic clamp) with the DI calculated from the hyperglycemic clamp alone (hcDI).

RESEARCH DESIGN AND METHODS

Complete data from hyperglycemic and hyperinsulinemic-euglycemic clamps were available for 330 youth: 73 normal weight, 168 obese with normal glucose tolerance, 57 obese with impaired glucose tolerance, and 32 obese with type 2 diabetes. The correlation between hcDI and 2cDI and Bland-Altman analysis of agreement between the two were examined.

RESULTS

Insulin sensitivity and first-phase insulin from hcDI showed a hyperbolic relationship. The hcDI correlated significantly with 2cDI in the groups combined (r = 0.85, P < 0.001) and within each group separately (r ≥ 62, P < 0.001). Similar to 2cDI, hcDI showed a declining pattern of β-cell function across the glucose-tolerance groups. Overall, hcDI values were 27% greater than 2cDI, due to the hyperglycemic versus euglycemic conditions, reflected in a positive bias with Bland-Altman analysis.

CONCLUSIONS

β-Cell function relative to insulin sensitivity could be accurately evaluated from a single hyperglycemic clamp, obviating the need for two separate clamp experiments, when lessening participant burden and reducing research costs are important considerations.The high prevalence of obesity and its associated comorbidity of glucose dysregulation in youth have increased the need for methods of assessing glucose-insulin dynamics in pediatric research (1,2). Insulin sensitivity and insulin secretion are impaired in obesity-associated dysglycemia (3,4). Insulin secretion is coupled to insulin sensitivity through a hyperbolic relationship; hence, insulin secretion is expressed relative to insulin sensitivity (i.e., the disposition index [DI]), to accurately assess β-cell function (5–7). When the clamp technique is used, which is accepted as the gold standard for the assessment of insulin sensitivity and secretion, the measurement of DI requires a hyperglycemic clamp to measure first-phase insulin and a hyperinsulinemic-euglycemic clamp, on a separate occasion, to measure insulin sensitivity (2). Owing to this need for two separate clamp experiments, measuring DI using the clamp methodology imposes significant participant burden in adults and children, but more so in the latter, and increases research costs, especially when repeated measurements are needed over time in longitudinal trials. Conversely, DI was first described and is commonly calculated from the frequently sampled intravenous glucose tolerance test (FSIVGTT), in which insulin sensitivity and acute insulin release are both measured from a single experiment (5,6,8). Mathematical modeling of DI (9,10), in addition to simple estimates of DI from the oral glucose tolerance test (OGTT) (11–13), has also been described. In the current study, we aimed to examine if DI calculated from a single hyperglycemic clamp, delivering both measures of insulin sensitivity and first-phase insulin, could provide an adequate measure of β-cell function relative to insulin sensitivity compared with DI derived from two clamps, a hyperinsulinemic-euglycemic clamp for insulin sensitivity and a hyperglycemic clamp for first-phase insulin secretion (2,14,15).     

A Randomized,Controlled Study of Once-Daily LY2605541, a Novel Long-Acting Basal Insulin,Versus Insulin Glargine in Basal Insulin–Treated Patients With Type 2 Diabetes

OBJECTIVE

To evaluate whether LY2605541 results in lower fasting blood glucose (FBG) versus insulin glargine (GL).

RESEARCH DESIGN AND METHODS

This 12-week, randomized, open-label, Phase 2 study enrolled patients with type 2 diabetes (hemoglobin A_1c [A1C] ≤ 10.5%), taking metformin and/or sulfonylurea with GL or NPH insulin once daily. Patients converted to morning insulin administration during lead-in were randomized 2:1 from GL (n = 248) or NPH insulin (n = 39) to LY2605541 (n = 195) or GL (n = 95) once daily in the morning.

RESULTS

At 12 weeks, FBG (mean ± SE) was similar with LY2605541 and GL (118.2 ± 2.0 mg/dL [6.6 ± 0.1 mmol/L] vs. 116.9 ± 2.7 mg/dL [6.5 ± 0.2 mmol/L], P = 0.433) as was A1C (7.0 ± 0.1 vs. 7.2 ± 0.1%, P = 0.279). Intraday blood glucose variability was reduced with LY2605541 (34.4 vs. 39.1 mg/dL [1.9 vs. 2.2 mmol/L], P = 0.031). LY2605541 patients had weight loss (−0.6 ± 0.2 kg, P = 0.007), whereas GL patients gained weight (0.3 ± 0.2 kg, P = 0.662; treatment difference: −0.8 kg, P = 0.001). The incidence and rate of both total hypoglycemia and nocturnal hypoglycemia were comparable between LY2605541 and GL, although, LY2605541 had a 48% reduction in nocturnal hypoglycemia after adjusting for baseline hypoglycemia (P = 0.021). Adverse events were similar across treatments. Alanine aminotransferase and aspartate aminotransferase remained within normal range but were significantly higher with LY2605541 (P ≤ 0.001).

CONCLUSIONS

In patients with type 2 diabetes, LY2605541 and GL had comparable glucose control and total hypoglycemia rates, but LY2605541 showed reduced intraday variability, lower nocturnal hypoglycemia, and weight loss relative to GL.Basal insulin in combination with oral antidiabetes medications (OADs) has been a successful initial insulin therapy for type 2 diabetes treatment (1–4). Once-daily analog basal insulins have a comparable glycemic-lowering effect and reduce nocturnal hypoglycemia rates relative to NPH insulin (1,5). This reduced risk for hypoglycemia, as well as a reduction in the need for twice-daily injections, has been attributed to the prolongation of action by retarding subcutaneous absorption, lessening peak activity, and reducing variability of circulating insulin levels. However, the peripheral subcutaneous administration of these insulin analogs does not replicate the twofold higher portal-versus-systemic circulating insulin levels seen with endogenously secreted insulin. Therefore, the net effect of peripheral insulin administration is potentially overstimulation of glucose uptake to compensate for the reduced hepatic insulin action needed to maintain glucose homeostasis.The basal insulin analog LY2605541 is a novel, long-acting insulin that consists of insulin lispro modified with a 20-kDa polyethylene glycol (PEG) moiety having a large hydrodynamic size which delays insulin absorption and reduces clearance, resulting in prolonged duration of action. The increase in functional molecular size appears to alter the distribution of this insulin to tissues. Hypothetically, the fenestrated hepatic sinusoidal endothelium may facilitate greater transport of LY2605541 into the liver relative to peripheral tissues (i.e., muscle and fat), potentially providing a more preferential hepatic action akin to normal physiology.This exploratory Phase 2 clinical trial was designed to compare the safety and efficacy of LY2605541 versus insulin glargine (GL) when administered once daily in the morning in combination with OADs for 12 weeks in patients with type 2 diabetes. The primary objective was to test the hypothesis that LY2605541 would result in lower fasting blood glucose (FBG) levels as measured by self-monitored blood glucose (SMBG) at end point (week 12) compared with GL.     

Adjusting Glucose-Stimulated Insulin Secretion for Adipose Insulin Resistance: An Index of β-Cell Function in Obese Adults

OBJECTIVE

The hyperbolic relationship between insulin secretion and sensitivity has been used to assess in vivo β-cell function (i.e., the disposition index). The disposition index emphasizes the importance of taking into account both skeletal muscle and hepatic insulin resistance to depict insulin secretion. However, we propose that adipose tissue insulin resistance also needs to be accounted for when characterizing glucose-stimulated insulin secretion (GSIS) because elevated plasma free fatty acids (FFAs) impair β-cell function.

RESEARCH DESIGN AND METHODS

To characterize the adipose disposition index, we used [1-¹⁴C] palmitate infusion to determine basal FFA turnover rate/adipose insulin resistance and an oral glucose tolerance test to characterize the first (i.e., 0–30 min) and second phase (i.e., 60–120 min) of GSIS. We validated a simplified version of the tracer infusion calculation as the product of (1/plasma FFA concentration × plasma insulin concentration) × GSIS in 44 obese insulin-resistant subjects.

RESULTS

The plasma FFA and palmitate tracer infusion calculations of the first- and second-phase disposition index were strongly correlated (r = 0.86, P < 0.000001 and r = 0.89, P < 0.000001, respectively). The first- and second-phase adipose disposition index derived from plasma FFA also was tightly associated with fasting hyperglycemia (r = −0.87, P < 0.00001 and r = −0.89, P < 0.00001, respectively) and 2-h glucose concentrations (r = −0.86, P < 0.00001 and r = −0.90, P < 0.00001).

CONCLUSIONS

Adjusting GSIS for adipose insulin resistance provides an index of β-cell function in obese subjects across the glucose spectrum. Plasma FFA–derived calculations of β-cell function may provide additional insight into the role of adipose tissue in glucose regulation.     

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).     

One-Hour Plasma Glucose Identifies Insulin Resistance and ��-Cell Dysfunction in Individuals With Normal Glucose Tolerance: Cross-sectional data from the Relationship between Insulin Sensitivity and Cardiovascular Risk (RISC) study

OBJECTIVE

Some individuals with normal glucose tolerance (NGT) exhibit a 1-h excursion of plasma glucose during oral glucose tolerance testing as high as that of individuals with impaired glucose tolerance (IGT). The aim of this study was to characterize their metabolic phenotype.

RESEARCH DESIGN AND METHODS

A total of 1,205 healthy volunteers (aged 29–61 years) underwent assessment of 1) oral glucose tolerance and 2) insulin sensitivity (standardized euglycemic-hyperinsulinemic clamp), as part of the Relationship between Insulin Sensitivity and Cardiovascular Risk (RISC) study.

RESULTS

One-hour plasma glucose correlated better than 2-h plasma glucose with total insulin secretion (r = 0.43), β-cell glucose sensitivity (r = −0.46), and β-cell rate sensitivity (r = −0.18). Receiver operating characteristic analysis identified 8.95 mmol/l as the best cutoff value for prediction of IGT from 1-h plasma glucose (sensitivity 77% and specificity 80%). Participants with NGT with 1-h plasma glucose >8.95 mmol/l had larger waist circumference, higher BMI, lower insulin sensitivity, higher fasting glucose, and higher insulin secretion than their counterparts with 1-h plasma glucose ≤8.95 mmol/l (P < 0.001 for all comparisons). Moreover, they exhibited lower β-cell glucose sensitivity (P < 0.001), β-cell rate sensitivity (P < 0.001), and potentiation factor (P = 0.026). When compared with conventionally defined IGT, they were not different in waist circumference and BMI, hepatic insulin extraction, β-cell glucose sensitivity, β-cell rate sensitivity, and potentiation factor but did have greater insulin sensitivity along with reduced basal (P = 0.001) and total insulin secretion (P = 0.002).

CONCLUSIONS

Higher values of 1-h plasma glucose may identify an intermediate condition between NGT and IGT characterized by greater insulin resistance, reduced β-cell glucose sensitivity, and reduced β-cell rate sensitivity.Impaired glucose tolerance (IGT) and impaired fasting glucose (IFG) are states of carbohydrate metabolism intermediate between normal glucose tolerance (NGT) and type 2 diabetes, which represent two partially overlapping conditions with distinct metabolic characteristics (1,2). In IFG, there is marked hepatic insulin resistance with near-normal muscle insulin sensitivity, whereas this pattern is reversed in IGT (2). Although both conditions are characterized by reduced early-phase insulin secretion, there is an additional impairment of late-phase insulin secretion in IGT. Accordingly, individuals with IGT have a rapid early (30 min) rise in plasma glucose during an oral glucose tolerance test (OGTT) which continues to rise until 60 min (1-h plasma glucose) and thereafter remains ≥7.8 mmol/l (140 mg/dl) at 120 min (2-h plasma glucose).As longitudinal studies have demonstrated that 40% of patients who develop type 2 diabetes after 10 years have NGT at baseline (1), there may be additional information beyond conventional IFG/IGT categories that may better discriminate future progression to type 2 diabetes (3). We have noted a subset of individuals with NGT who have early glucose excursions during an OGTT as high as those observed in individuals with IGT. However, because plasma glucose concentrations decline adequately by 2 h, due to preservation of late-phase insulin secretion, these individuals do not have, by current definitions, any form of disordered carbohydrate metabolism (4). Data from the San Antonio Study have shown that β-cell glucose sensitivity and insulin sensitivity contribute to values of 2-h plasma glucose independently of each other (5); thus, we hypothesized that individuals with NGT with 1-h plasma glucose levels as high as in those with IGT might represent an intermediate phenotype of abnormal carbohydrate metabolism with either impaired insulin sensitivity or β-cell glucose sensitivity, who are potentially at increased risk of progression to type 2 diabetes.To investigate this hypothesis we analyzed cross-sectional data from the European Relationship between Insulin Sensitivity and Cardiovascular Risk (RISC) study (6), examining the metabolic phenotype of individuals with NGT who had high 1-h plasma glucose excursions. We aimed to identify a new glucose tolerance subgroup who might benefit from targeted lifestyle advice and/or pharmacological intervention.     

Crystal Structures of KPC-2 and SHV-1 β-Lactamases in Complex with the Boronic Acid Transition State Analog S02030

Resistance to expanded-spectrum cephalosporins and carbapenems has rendered certain strains of Klebsiella pneumoniae the most problematic pathogens infecting patients in the hospital and community. This broad-spectrum resistance to β-lactamases emerges in part via the expression of KPC-2 and SHV-1 β-lactamases and variants thereof. KPC-2 carbapenemase is particularly worrisome, as the genetic determinant encoding this β-lactamase is rapidly spread via plasmids. Moreover, KPC-2, a class A enzyme, is difficult to inhibit with mechanism-based inactivators (e.g., clavulanate). In order to develop new β-lactamase inhibitors (BLIs) to add to the limited available armamentarium that can inhibit KPC-2, we have structurally probed the boronic acid transition state analog {"type":"entrez-protein","attrs":{"text":"S02030","term_id":"83679","term_text":"pir||S02030"}}S02030 for its inhibition of KPC-2 and SHV-1. {"type":"entrez-protein","attrs":{"text":"S02030","term_id":"83679","term_text":"pir||S02030"}}S02030 contains a boronic acid, a thiophene, and a carboxyl triazole moiety. We present here the 1.54- and 1.87-Å resolution crystal structures of {"type":"entrez-protein","attrs":{"text":"S02030","term_id":"83679","term_text":"pir||S02030"}}S02030 bound to SHV-1 and KPC-2 β-lactamases, respectively, as well as a comparative analysis of the {"type":"entrez-protein","attrs":{"text":"S02030","term_id":"83679","term_text":"pir||S02030"}}S02030 binding modes, including a previously determined {"type":"entrez-protein","attrs":{"text":"S02030","term_id":"83679","term_text":"pir||S02030"}}S02030 class C ADC-7 β-lactamase complex. {"type":"entrez-protein","attrs":{"text":"S02030","term_id":"83679","term_text":"pir||S02030"}}S02030 is able to inhibit vastly different serine β-lactamases by interacting with the conserved features of these active sites, which includes (i) forming the bond with catalytic serine via the boron atom, (ii) positioning one of the boronic acid oxygens in the oxyanion hole, and (iii) utilizing its amide moiety to make conserved interactions across the width of the active site. In addition, {"type":"entrez-protein","attrs":{"text":"S02030","term_id":"83679","term_text":"pir||S02030"}}S02030 is able to overcome more distantly located structural differences between the β-lactamases. This unique feature is achieved by repositioning the more polar carboxyl-triazole moiety, generated by click chemistry, to create polar interactions as well as reorient the more hydrophobic thiophene moiety. The former is aided by the unusual polar nature of the triazole ring, allowing it to potentially form a unique C—H…O 2.9-Å hydrogen bond with S130 in KPC-2.     

Declining ��-Cell Function Relative to Insulin Sensitivity With Increasing Fasting Glucose Levels in the Nondiabetic Range in Children

OBJECTIVE

In adults, higher fasting plasma glucose (FPG) levels, even within the normoglycemic range, are associated with increased diabetes risk. This investigation tested the hypothesis that β-cell function relative to insulin sensitivity decreases with increasing FPG in youth.

RESEARCH DESIGN AND METHODS

A total of 223 youth with FPG <126 mg/dl underwent evaluation of first- and second-phase insulin secretion during a 2-h hyperglycemic (∼225 mg/dl) clamp, insulin sensitivity during a 3-h hyperinsulinemic-euglycemic clamp, body composition, and abdominal adiposity with dual-energy X-ray absorptiometry and computed tomographic scan. β-Cell function relative to insulin sensitivity was calculated as the product of first-phase insulin and insulin sensitivity, i.e., glucose disposition index (GDI). The subjects were divided into three FPG categories: ≤90, >90–<100, and ≥100–<126 mg/dl.

RESULTS

GDI decreased significantly across the three categories as FPG increased (1,086 ± 192 vs. 814 ± 67 and 454 ± 57 mg/kg/min, P = 0.002). This decline remained significant after adjustment for race, sex, BMI, and percent body fat or visceral fat. Within each FPG category, GDI declined with increasing BMI percentiles.

CONCLUSIONS

The impairment in β-cell function relative to insulin sensitivity is apparent even within the nondiabetic FPG range in children. At the current cutoff of 100 mg/dl for impaired fasting glucose (IFG), there is an ∼49% decline in the GDI independent of obesity and race. This observation may reflect a heightened risk of β-cell dysfunction and progression to diabetes in these children. Considering the near doubling of IFG prevalence among youth between National Health and Nutrition Examination Survey 1999–2000 and 2005–2006, our findings have important public health implications.Higher fasting plasma glucose (FPG) levels within the currently accepted normoglycemic range seem to have an impact on diabetes risk in adults (1–3). FPG levels >125 mg/dl indicate a provisional diagnosis of diabetes (4). FPG levels below this cutoff but above normal increase the risk of developing diabetes (5) and are associated with a higher cardiovascular disease risk (6,7). The American Diabetes Association classifies this intermediate state of FPG as impaired fasting glucose (IFG) (4) and initially defined it as fasting glucose of 110–125 mg/dl (8), which was lowered to 100 mg/dl in 2003 to better identify subjects at risk of diabetes development (9). Several studies in adults suggested that future diabetes risk increases continually with increasing FPG even below this lower cutoff for normoglycemia (1,2). In adults, fasting glucose levels of 90–94 mg/dl conferred a 49% greater risk of developing diabetes compared with levels <85 mg/dl (2). FPG levels in the top quintiles (95–99 mg/dl) of the normoglycemic range constituted an independent risk factor for type 2 diabetes among young men in the Israeli army after adjustment for several risk factors (1). In a Mauritius population-based study, parameters related to diabetes and cardiovascular disease such as higher BMI, cholesterol, triglycerides, and hypertension were positively correlated with higher FPG values in an approximately linear relationship (3). In addition, a meta-analysis of prospective studies showed a continuous relationship between baseline fasting glucose and subsequent cardiovascular risk (10). These observations raise a fundamental question: are insulin secretion and sensitivity impaired at higher levels of FPG but within the normal range? Few studies in adults have investigated this question, and results are conflicting (11–13). However, none of these studies used robust methodologies of assessing in vivo insulin secretion and sensitivity to derive a glucose disposition index (GDI), which is accepted to be the best indicator of β-cell dysfunction (14). Currently there are no published data assessing the relationship between high-normal fasting glucose levels and insulin sensitivity and secretion in children. The pre-diabetes cutoff levels for FPG in pediatrics are based on adult data and not on data generated in pediatric populations.In this study, we investigated the relationship between levels of fasting glucose and insulin secretion relative to insulin sensitivity, i.e., GDI, in children. Based on adult observations we hypothesized that β-cell function relative to insulin sensitivity decreases as FPG concentrations increase within the currently accepted nondiabetic range in children.