ARA290 Improves Insulin Release and Glucose Tolerance in Type 2 Diabetic Goto-Kakizaki Rats

Effects of ARA290 on glucose homeostasis were studied in type 2 diabetic Goto-Kakizaki (GK) rats. In GK rats receiving ARA290 daily for up to 4 wks, plasma glucose concentrations were lower after 3 and 4 wks, and hemoglobin A_1c (Hb A_1c) was reduced by ~20% without changes in whole body and hepatic insulin sensitivity. Glucose-stimulated insulin secretion was increased in islets from ARA290-treated rats. Additionally, in response to glucose, carbachol and KCl, islet cytoplasmic free Ca²⁺ concentrations, [Ca²⁺]_i, were higher and the frequency of [Ca²⁺]_i oscillations enhanced compared with placebo. ARA290 also improved stimulus–secretion coupling for glucose in GK rat islets, as shown by an improved glucose oxidation rate, ATP production and acutely enhanced glucose-stimulated insulin secretion. ARA290 also exerted an effect distal to the ATP-sensitive potassium (K_ATP) channel on the insulin exocytotic pathway, since the insulin response was improved following islet depolarization by KCl when K_ATP channels were kept open by diazoxide. Finally, inhibition of protein kinase A completely abolished effects of ARA290 on insulin secretion. In conclusion, ARA290 improved glucose tolerance without affecting hematocrit in diabetic GK rats. This effect appears to be due to improved β-cell glucose metabolism and [Ca²⁺]_i handling, and thereby enhanced glucose-induced insulin release.     

Safety and Efficacy of ARA 290 in Sarcoidosis Patients with Symptoms of Small Fiber Neuropathy: A Randomized,Double-Blind Pilot Study

ARA 290 (a peptide designed to activate the innate repair receptor that arrests injury and initiates cytoprotection, antiinflammation and healing) reduces allodynia in preclinical neuropathy models. We studied the safety and efficacy of ARA 290 to reduce symptoms of small fiber neuropathy (SFN) in patients with sarcoidosis. A total of 22 patients diagnosed with sarcoidosis and symptoms of SFN were enrolled in a double-blind, placebo-controlled exploratory trial consisting of three times weekly intravenous dosing of ARA 290 (2 mg; n = 12) or placebo (n = 10) for 4 wks. Inclusion criteria were a diagnosis of neuropathy and a spontaneous pain score of ≥5 (Brief Pain Inventory [BPI]). Endpoints assessed were changes in pain intensity and the small fiber neuropathy screening list (SFNSL) score, quality of life (SF-36), depressive symptoms (Inventory of Depressive Symptomatology [IDS]) and fatigue (Fatigue Assessment Scale [FAS]). No safety concerns were raised by clinical or laboratory assessments. The ARA 290 group showed significant (p < 0.05) improvement at wk 4 in SFNSL score compared with placebo (Δ −11.5 ± 3.04 versus Δ −2.9 ± 3.34 [standard error of the mean]). Additionally, the ARA 290 group showed a significant change from baseline in the pain and physical functioning dimensions of the SF-36 (Δ −23.4 ± 5.5 and Δ −14.6 ± 3.9, respectively). The mean BPI and FAS scores improved significantly but equivalently in both patient groups. No change was observed in the IDS. ARA 290 appears to be safe in patients with sarcoidosis and can reduce neuropathic symptoms.     

The erythropoietin analogue ARA290 modulates the innate immune response and reduces Escherichia coli invasion into urothelial cells

Urinary tract infections (UTI) are one of the most common infectious diseases worldwide. The majority is caused by uropathogenic Escherichia coli. Emerging resistances against conventional antimicrobial therapy requires novel treatment strategies. Beside its role in erythropoiesis, erythropoietin has been recognized to exert tissue-protective and immunomodulatory properties. Here, we investigated the nonerythropoietic erythropoietin analogue ARA290 for potential properties to modulate uroepithelial infection by E. coli in a cell culture model. Expression of the erythropoietin receptor was increased by bacterial stimuli and further enhanced by ARA290 in bladder epithelial cell lines and primary cells as well as in the monocytic cell line THP-1. Stimulation with ARA290 promoted an immune response, inducing a strong initial, but temporarily limited interleukin-8 induction. Moreover, the invasion of bladder epithelial cells by E. coli was significantly reduced in cells costimulated with ARA290. Our results indicate that the erythropoietin analogue ARA290 might be a candidate for the development of novel treatment strategies against UTI, by boosting an early immune response and reducing bacterial invasion as a putative source for recurrent infections.     

Fructosamine Is a Useful Indicator of Hyperglycaemia and Glucose Control in Clinical and Epidemiological Studies – Cross-Sectional and Longitudinal Experience from the AMORIS Cohort

Context

Fructosamine is a glycemic biomarker which may be useful for indication and control of diabetes respectively.

Objective

The objective of the study was to evaluate fructosamine as an indicator of hyperglycaemia and glucose control in subjects with diabetes.

Design, Setting & Patients

From the AMORIS cohort, subjects with serum glucose, fructosamine and HbA_1c from the same examination were studied cross-sectionally and longitudinally (n = 10,987; 5,590 overnight-fasting). The guidelines of the American Diabetes Association were followed for classification of prediabetes and diabetes. Separate analyses were performed in patients with a newly detected or a known diagnosis of type 1 or type 2 diabetes respectively.

Results

All three biomarkers were strongly correlated. With regard to the association between fructosamine and HbA_1c Pearson linear correlation coefficients in the range of 0.67–0.75 were observed in fasting and non-fasting subjects with type 1 or type 2 diabetes. Analyses of glucose control in fasting patients with type 2 diabetes having all three biomarkers measured at three separate occasions within on average 290 days of the index examination showed similar trends over time for glucose, fructosamine and HbA_1c. Discrimination of subjects with and without diabetes across the range of fructosamine levels was good (area under curve (AUC) 0.91–0.95) and a fructosamine level of 2.5 mmol/L classified subjects to diabetes with a sensitivity of 61% and a specificity of 97%.

Conclusions

Fructosamine is closely associated with HbA_1c and glucose respectively and may be a useful biomarker of hyperglycaemia and glucose control in clinical and epidemiological studies.     

Corneal Confocal Microscopy Detects Neuropathy in Patients with Type 1 Diabetes without Retinopathy or Microalbuminuria

Objective

Corneal innervation is increasingly used as a surrogate marker of human diabetic peripheral neuropathy (DPN) however its temporal relationship with the other microvascular complications of diabetes is not fully established. In this cross-sectional, observational study we aimed to assess whether neuropathy occurred in patients with type 1 diabetes, without retinopathy or microalbuminuria.

Materials and Methods

All participants underwent detailed assessment of peripheral neuropathy [neuropathy disability score (NDS), vibration perception threshold (VPT), peroneal motor nerve conduction velocity (PMNCV), sural sensory nerve conduction velocity (SSNCV) and in vivo corneal confocal microscopy (IVCCM)], retinopathy (digital fundus photography) and albuminuria status [albumin: creatinine ratio (ACR)].

Results

53 patients with Type 1 diabetes with (n=37) and without retinopathy (n=16) were compared to control subjects (n=27). SSNCV, corneal nerve fibre (CNFD) and branch (CNBD) density and length (CNFL) were reduced significantly (p<0.001) in diabetic patients without retinopathy compared to control subjects. Furthermore, CNFD, CNBD and CNFL were also significantly (p<0.001) reduced in diabetic patients without microalbuminuria (n=39), compared to control subjects. Greater neuropathic severity was associated with established retinopathy and microalbuminuria.

Conclusions

IVCCM detects early small fibre damage in the absence of retinopathy or microalbuminuria in patients with Type 1 diabetes.     

HbA1c Alone Is a Poor Indicator of Cardiometabolic Risk in Middle-Aged Subjects with Pre-Diabetes but Is Suitable for Type 2 Diabetes Diagnosis: A Cross-Sectional Study

Objectives

Glycated haemoglobin A_1c (HbA_1c) measurement is recommended as an alternative to fasting plasma glucose (FPG) for the diagnosis of pre-diabetes and type 2 diabetes. However, evidence suggests discordance between HbA_1c and FPG. In this study we examine a range of metabolic risk features, pro-inflammatory cytokines, acute-phase response proteins, coagulation factors and white blood cell counts to determine which assay more accurately identifies individuals at increased cardiometabolic risk.

Materials and Methods

This was a cross-sectional study involving a random sample of 2,047 men and women aged 46-73 years. Binary and multinomial logistic regression were employed to examine risk feature associations with pre-diabetes [either HbA_1c levels 5.7-6.4% (39-46 mmol/mol) or impaired FPG levels 5.6-6.9 mmol/l] and type 2 diabetes [either HbA_1c levels >6.5% (>48 mmol/mol) or FPG levels >7.0 mmol/l]. Receiver operating characteristic curve analysis was used to evaluate the ability of HbA_1c to discriminate pre-diabetes and diabetes defined by FPG.

Results

Stronger associations with diabetes-related phenotypes were observed in pre-diabetic subjects diagnosed by FPG compared to those detected by HbA_1c. Individuals with type 2 diabetes exhibited cardiometabolic profiles that were broadly similar according to diagnosis by either assay. Pre-diabetic participants classified by both assays displayed a more pro-inflammatory, pro-atherogenic, hypertensive and insulin resistant profile. Odds ratios of having three or more metabolic syndrome features were also noticeably increased (OR: 4.0, 95% CI: 2.8-5.8) when compared to subjects diagnosed by either HbA_1c (OR: 1.4, 95% CI: 1.2-1.8) or FPG (OR: 3.0, 95% CI: 1.7-5.1) separately.

Conclusions

In middle-aged Caucasian-Europeans, HbA_1c alone is a poor indicator of cardiometabolic risk but is suitable for diagnosing diabetes. Combined use of HbA_1c and FPG may be of additional benefit for detecting individuals at highest odds of type 2 diabetes development.     

Ketamine Does Not Produce Relief of Neuropathic Pain in Mice Lacking the β-Common Receptor (CD131)

Neuropathic pain (NP) is a debilitating condition associated with traumatic, metabolic, autoimmune and neurological etiologies. Although the triggers for NP are diverse, there are common underlying pathways, including activation of immune cells in the spinal cord and up-regulation of the N-methyl-D-aspartate receptor (NMDAR). Ketamine, a well-known NDMAR antagonist, reduces neuropathic pain in a sustained manner. Recent study has shown that the novel 11-amino acid peptide erythropoietin derivative ARA290 produces a similar, long-lasting relief of NP. Here, we show that both drugs also have similar effects on the expression of mRNA of the NMDAR, as well as that of microglia, astrocytes and chemokine (C-C motif) ligand 2, all-important contributors to the development of NP. Although the effects of ketamine and ARA 290 on NP and its molecular mediators suggest a common mechanism of action, ARA 290 has no affinity for the NMDAR and acts specifically via the innate repair receptor (IRR) involved in tissue protection. We speculated therefore, that the IRR might be critically involved in the action of ketamine on neuropathic pain. To evaluate this, we studied the effects of ketamine and ARA 290 on acute pain, side effects, and allodynia following a spared nerve injury model in mice lacking the β-common receptor (βcR), a structural component of the IRR. Ketamine (50 mg/kg) and ARA 290 (30 µg/kg) produced divergent effects on acute pain: ketamine produced profound antinociception accompanied with psychomotor side effects, but ARA290 did not, in both normal and knock out mice. In contrast, while both drugs were antiallodynic in WT mice, they had no effect on NP in mice lacking the βcR. Together, these results show that an intact IRR is required for the effective treatment of NP with either ketamine or ARA 290, but is not involved in ketamine’s analgesic and side effects.     

Achieving further glycemic control in type 2 diabetes mellitus

Objectives To identify patients with type 2 diabetes mellitus who were in poor glycemic control and therapeutic adjustments that might improve control. Design Using electronic pharmacy data, we assigned subjects to 1 of 4 therapeutic categories. We then identified patients within each category who did not meet the recommended standard of glycemic control (glycosylated hemoglobin [Hb A_1c] <0.08 [<8.0%]) and studied their therapetic regimens for possible improvements. Subjects The subjects were 5,061 members of a large group-model health maintenance organization who had type 2 diabetes and 12 months of 1997 health plan eligibility. Main outcome measures The dosage of antihyperglycemic agents (sulfonylureas, metformin, and insulin) in relation to glycemic control as measured by the Hb A_1c. Results A significant number (n = 1,570 [31.0%]) of persons with type 2 diabetes might improve their glycemic control with simple adjustments to their pharmacologic therapy. Conclusion Busy clinicians with heavy workloads can improve their management of diabetes by identifying patients whose glycemic control could be improved through a change in medication or simple adjustment in dosage.     

Markedly Low Hemoglobin A1c in a Patient with an Unusual Presentation of ß-Thalassemia Minor

ObjectiveTo describe very low hemoglobin A_1c levels in a patient with type 2 diabetes mellitus and an unusual presentation of β-thalassemia minor.MethodsWe present the clinical and laboratory findings of the study patient.ResultsA 64-year-old African American man with type 2 diabetes mellitus was referred to the endocrinology clinic with a hemoglobin A_1c level of 1.6% despite elevated blood glucose concentrations. A red blood cell survival study with chromium-51 revealed that he had a reduced erythrocyte life span less than 25% of normal. He also had a markedly elevated reticulocyte count ranging from 236 to 534 x 10³/μL (reference range, 25-75 x 103/μL). The laboratory findings, which are not characteristic of ß-thalassemia minor, could be the cause of the markedly low hemoglobin A_1c in this patient.ConclusionsAlthough rare, when associated with marked erythrocyte turnover, β-thalassemia minor can lead to a severe reduction in HbA_1c levels. In this scenario, glycemic control is best assessed by measuring fructosamine. (Endocr Pract. 2010;16:89-92)     

Impact of Race/Ethnicity on the Efficacy and Safety of Commonly used Insulin Regimens: A Post HOC Analysis of Clinical Trials in Type 2 Diabetes Mellitus

ObjectiveTo explore the impact of race/ethnicity on the efficacy and safety of commonly used insulin regimens in patients with type 2 diabetes mellitus.MethodsIn this post hoc analysis, pooled data from 11 multinational clinical trials involving 1455 patients with type 2 diabetes were used to compare specific insulin treatments in Latino/Hispanic, Asian, African-descent, and Caucasian patients. Insulin treatments included once daily insulin glargine or neutral protamine Hagedorn (BASAL), insulin lispro mix 75/25 twice daily (LMBID), or insulin lispro mix 50/50 three times daily (LMTID).ResultsRace/ethnicity was associated with significant outcome differences for each of the insulin regimens. BASAL therapy was associated with greater improvement in several measures of glycemic control among Latino/Hispanic patients compared with Caucasian patients (lower end point hemoglobin A1c, greater reduction in hemoglobin A1c from baseline, and a larger proportion of patients achieving hemoglobin A1c level < 7%). In contrast, LMBID therapy was associated with higher end point hemoglobin A_1c and a smaller decrease in hemoglobin A_1c from baseline in Latino/Hispanic and Asian patients than in Caucasian patients. Furthermore, fewer Asian patients attained a hemoglobin A_1c level < 7% than did Caucasians patients. For LMTID therapy, hemoglobin A_1c outcomes were comparable across patient groups. Fasting blood glucose and glycemic excursions varied among racial/ethnic groups for the 3 insulin regimens. Weight change was comparable among racial/ethnic groups in each insulin regimen. During treatment with LMTID, Asian patients experienced higher incidence and rate of severe hypoglycemia than Caucasian patients.ConclusionsLatino/Hispanic, Asian, and African-descent patients with type 2 diabetes show different metabolic responses to insulin therapy, dependent in part on insulin type and regimen intensity. (Endocr Pract. 2010: 818-828:pp)     

Effect of Pramlintide on Weight in Overweight and Obese Insulin‐Treated Type 2 Diabetes Patients

Objective: Several randomized, placebo‐controlled, double‐blind trials in insulin‐treated patients with type 2 diabetes have shown that adjunctive therapy with pramlintide reduces hemoglobin (Hb)A_1c with concomitant weight loss. This analysis further characterizes the weight‐lowering effect of pramlintide in this patient population. Research Methods and Procedures: This pooled post hoc analysis of two long‐term trials included all patients who were overweight/obese at baseline (BMI > 25 kg/m²), and who were treated with either 120 μg pramlintide BID (n = 254; HbA_1c 9.2%; weight, 96.1 kg) or placebo (n = 244; HbA_1c 9.4%; weight, 95.0 kg). Statistical endpoints included changes from baseline to week 26 in HbA_1c, body weight, and insulin use. Results: Pramlintide treatment resulted in significant reductions from baseline to week 26, compared with placebo, in HbA_1c and body weight (both, p < 0.0001), for placebo‐corrected reductions of ?0.41% and ?1.8 kg, respectively. Approximately three times the number of patients using pramlintide experienced a ≥5% reduction of body weight than with placebo (9% vs. 3%, p = 0.0005). Patients using pramlintide also experienced a proportionate decrease in total daily insulin use (r = 0.39, p < 0.0001). The greatest placebo‐corrected reductions in weight at week 26 were observed in pramlintide‐treated patients with a BMI >40 kg/m² and in those concomitantly treated with metformin (both, p < 0.001), for placebo‐corrected reductions of ?3.2 kg and ?2.5 kg, respectively. Discussion: These findings support further evaluation of the weight‐lowering potential of pramlintide in obese patients with type 2 diabetes.     

Chromium Effects on Glucose Tolerance and Insulin Sensitivity in Persons at Risk for Diabetes Mellitus

ObjectiveTo investigate the effects of daily chromium picolinate supplementation on serum measures of glucose tolerance and insulin sensitivity in patients at high risk for type 2 diabetes mellitus.MethodsWe conducted a randomized, double-blind, placebo-controlled, modified cross-over clinical trial with 6-month sequences of intervention and placebo followed by a 6-month postintervention assessment. Adult patients with impaired fasting glucose, impaired glucose tolerance, or metabolic syndrome were enrolled. Participants received 6-month sequences of chromium picolinate or placebo at 1 of 2 dosages (500 or 1000 mcg daily). Primary outcome measures were change in fasting plasma glucose, 2-hour plasma glucose during oral glucose tolerance testing, fasting and 2-hour insulin, and homeostasis model assessment of insulin resistance (HOMA-IR). Secondary outcomes included anthropometric measures, blood pressure, endothelial function, hemoglobin A_1c, lipids, and urinary microalbumin.ResultsFifty-nine participants were enrolled. No changes were seen in glucose level, insulin level, or HOMA-IR (all P > .05) after 6 months of chromium at either dosage level (500 mcg or 1000 mcg daily) when compared with placebo. None of the secondary outcomes improved with either chromium dosage compared with placebo (P > .05).ConclusionsChromium supplementation does not appear to ameliorate insulin resistance or impaired glucose metabolism in patients at risk for type 2 diabetes and thus is unlikely to attenuate diabetes risk. (Endocr Pract. 2011;17:16-25)     

Nicotinamide Effects Oxidative Burst Activity of Neutrophils in Patients with Poorly Controlled Type 2 Diabetes Mellitus

Neutrophil functions are impaired in patients with diabetes mellitus. Bacterial phagocytosis and oxidative burst activity are reduced at high glucose concentrations in diabetic patients. Defects in neutrophil oxidative burst capacity are of multifactorial origin in diabetes mellitus and correlate with glucose levels. It has been reported that neutrophil NADPH oxidase activity is impaired and superoxide production is reduced in diabetic patients with or without any infections. Nicotinamide is a vitamin B3 derivative and a NAD precursor with immunomodulatory effects. In vitro studies demonstrated that nicotinamide increases NAD and NADH content of beta cells. The authors hypothesized that nicotinamide may restore the impaired oxidative burst capacity of neutrophils in diabetic patients by increasing the NADH content as an electron donor and possibly through NADPH oxidase activity of the cell. In order to test the hypothesis, this placebo-controlled and open study was designed to evaluate neutrophil functions in infection-free poorly controlled type 2 diabetic patients as compared to healthy subjects and assess the effects of nicotinamide on neutrophil phagocytosis as well as oxidative burst activity. Thirty patients with type 2 diabetes mellitus were enrolled in the study. Sixteen were females and 14 were males, with a mean age 58 ± 10. All patients were on sulphonylurea treatment and their hemoglobin A_1c (HbA_1c) levels were above 7.5%. The control group consisted of 10 voluntary healthy subjects. Diabetic and control subjects were not significantly different in terms of age, body mass index (BMI), leucocyte and neutrophil counts, C-reactive protein (CRP) level, and erythrocyte sedimentation rate (ESR), but HbA_1c and fasting glucose levels were significantly higher in patients with diabetes mellitus. Phagocytic activity and respiratory burst indexes were measured by flow cytometric analyses as previously described by Rothe and Valet (Methods Enzyml., 233, 539–548, 1994) and compared in diabetic subjects and healthy controls. Diabetic patients were grouped to receive either 50 mg/kg oral nicotinamide (n = 15) or placebo (n = 15) for a period of 1 month. The 2 groups did not differ in terms of treatment, frequency of hypertension, BMI, diabetes duration, age, fasting plasma glucose (FPG), HbA_1c, CRP, ESR, polymorphonuclear leukocyte (PNL) and neutrophil counts. Neutrophil functions were reassessed after the treatment period. Phagocytic activity represented as indexes were lower in diabetic patients when compared to healthy subjects, but the differences were not statistically significant (P > .05). Patients with diabetes mellitus had significantly lower oxidative burst indexes when compared to healthy controls (P values < .05). In diabetic patients, a negative correlation between neutrophil functions and HbA_1c was found which was not statistically significant (P values > .05). Phagocytic indexes were similar in nicotinamide and placebo groups after treatment period (P > .05). But oxidative burst activity in patients receiving nicotinamide was greater when compared with placebo and the difference was statistically significant at 30 and 45 minutes (P values .04 and .03). This effect of nicotinamide may be due to increased NADH content and NADPH oxidase activity of the cell, which needs to be further studied. Impaired neutrophil functions may aggravate various infections in patients with diabetes mellitus and blood glucose regulation is an important target of treatment to improve neutrophil functions. But nicotinamide treatment may help to improve prognosis in diabetic patients with severe infections.     

Association analysis of TNFRSF1B polymorphisms with type 2 diabetes and its related traits in North India

Inflammation plays a crucial role in the pathogenesis of type 2 diabetes and various lines of evidences suggest an important contribution of type 2 receptor for TNFα (TNFR2), a mediator of inflammatory responses. Though genetic association of TNFRSF1B (encoding TNFR2) polymorphisms have been investigated in various studies, their involvement is not clear because of inconsistent findings. Because of high susceptibility of Indian population to type 2 diabetes and its complications, we evaluated the association of TNFRSF1B polymorphisms-rs1061622 (M196R; exon6) and rs3397 (3′UTR) and (CA) _n repeat (intron 4) in 1,852 subjects including 1,040 cases and 812 controls with type 2 diabetes and its associated peripheral neuropathy and hypertension in North Indians of Indo-European ethnicity. The allelic and genotypic distributions of these polymorphisms were comparable among healthy control vs. type 2 diabetes, peripheral neuropathy vs. non-neuropathy and hypertensive vs. normotensive groups. (CA) _n polymorphism has been shown to be associated with diabetic neuropathy in Caucasians, however, this could not be replicated in our study (P = 0.27). None of the polymorphisms were found to influence the 14 anthropometric and biochemical traits related to type 2 diabetes studied here. Thus, we conclude that TNFRSF1B is not a major contributing factor to the genetic risk of type 2 diabetes, its associated peripheral neuropathy and hypertension and related metabolic traits in North Indians.     

Sensorineural Hearing Loss-A Common Finding in Early-Onset Type 2 Diabetes Me Llitus

ObjectiveTo evaluate the prevalence and potential associations of hearing impairment in patients 30 to 50 years old with diabetes diagnosed before age 40 years— early-onset type 2 diabetes mellitus (T2DM).MethodsThe study cohorts consisted of 46 consecutive patients with early-onset T2DM and 47 agematched control subjects with rheumatoid arthritis. All study subjects completed clinical, serologic, and auditory assessments.ResultsThe patients with T2DM had a mean age of 42 ± 6 years and a mean disease duration of 11 ± 6 years. Microalbuminuria was present in 26.1%, proliferative retinopathy in 26.1%, and symptomatic peripheral neuropathy in 23.9%. The prevalence of unilateral or bilateral hearing loss was significantly higher in the patients with T2DM than in the patients with rheumatoid arthritis (21.7% versus 6.4%, respectively; P = .01). Most cases of hearing loss were mild and involved high or acute tones. After multivariate analysis with adjustment for age, there was a significant association between hearing loss and hemoglobin A_1c (odds ratio, 1.3; 95% confidence interval, 1.02 to 1.81; P = .035). In the patients with T2DM, the lengthening of the brainstem response was not significantly increased; however, the wave morphologic features were abnormal and the reproducibility was poor in both ears in 11 patients (24%).ConclusionPatients with early-onset T2DM and poor glycemic control have an increased prevalence of subclinical hearing loss and impaired auditory brainstem responses. Hearing impairment may be an underrecognized complication of diabetes. (Endocr Pract. 2012;18:549-557)     

Influence of chromium-enriched yeast on blood glucose and insulin variables, blood lipids, and markers of oxidative stress in subjects with type 2 diabetes mellitus

The aim of this study was to determine the effect of chromium (Cr)-enriched yeast on blood glucose and insulin variables, blood lipids, and blood markers of oxidative stress in persons with type 2 diabetes mellitus (median duration: 3.0 yr). Thirty-six subjects (9 men, 27 women; mean age: 61.3 yr; mean body mass index: 34.33 kg/m²) were supplemented with 400 μg Cr/d as Cr-enriched yeast (n=19) or placebo (n=17) for 12 wk in a randomized, double-blind study. The most interesting results were obtained by comparison of the change in the placebo group to the change in the Cr group. The Cr group showed a significantly greater increase in serum Cr compared to the placebo group (p<0.05). Supplementation with Cr-enriched yeast was associated with a significant decrease in fasting serum glucose compared to placebo (p<0.01). Blood markers of oxidative stress glutathione peroxidase activity and levels of reduced glutathione were essentially unchanged in the Cr group after 12 wk, but decreased significantly in the placebo group (p<0.05, p<0.01, respectively), Serum HbA_1c and glycated protein (fructosamine) were essentially unchanged in the Cr group, whereas HbA_1c tended to increase in the placebo group (from 6.94% to 7.11%). Fasting serum insulin decreased in both groups, with a greater tendency in the Cr group (−16.5% vs −9.5%). These data suggest that supplementation of well-controlled type 2 diabetics with Cr-enriched yeast is safe and can result in improvements in blood glucose variables and oxidative stress.     

Ethnic disparity in hemoglobin A1c levels among normoglycemic offspring of parents with type 2 diabetes mellitus

ObjectiveTo investigate the racial/ethnic disparities in hemoglobin A_1c levels among nondiabetic persons with similar parental history of type 2 diabetes mellitus.MethodsWe studied a community-based sample of adult offspring of parents with type 2 diabetes mellitus. Measurements included anthropometry, hematology assessments, serial fasting plasma glucose, oral glucose tolerance testing, plasma insulin, hemoglobin A_1c, insulin sensitivity, and b-cell function, using a homeostasis model assessment.ResultsThe study included 302 participants (135 white, 167 black). Compared with white participants, black participants had lower fasting plasma glucose levels (91.9 ± 0.51 mg/dL vs 93.6 ± 0.50 mg/dL, P = .015), lower area under the curve of plasma glucose during oral glucose tolerance testing (P = <.001), higher body mass index (31.1 ± 0.61 kg/m² vs 28.5 ± 0.57 kg/m², P = <.001), and similar insulin sensitivity and b-cell function. Hemoglobin A_1c was higher in black participants than in white participants (5.68 ± 0.033% vs 5.45 ± 0.028%, P <.001). The absolute black-white difference in hemoglobin A_1c level of approximately 0.22% persisted after adjusting for age, hemoglobin, hematocrit, body mass index, waist circumference, fasting plasma glucose, glucose area under the curve, and other covariates.ConclusionsAmong healthy offspring of parents with type 2 diabetes mellitus in this study, African American participants had higher hemoglobin A_1c levels than white participants after adjusting for age, adiposity, blood glucose, and known variables. Thus, plasma glucose level is more valid than hemoglobin A_1c for diagnosing prediabetes or diabetes in black persons. (Endocr Pract. 2012; 18:356-362)     

Self-Assessment of Sexual Maturation in Children and Adolescents with Diabetes Mellitus

ObjectiveTo evaluate the reliability of a self-assessment tool as a surrogate means for estimating phase of sexual maturation in children and adolescents with diabetes mellitus.MethodsChildren and adolescents between 8 and 16 years of age with the diagnosis of type 1 or type 2 diabetes mellitus were recruited from the pediatric endocrinology clinic at a children’s hospital. Participants were given a series of gender-appropriate drawings representing the 5 Tanner stages of sexual maturation for genital development in boys and breast and genital development in girls and asked to select the illustration that best represented their current maturity stage. The self-assessments were compared with physical examination findings by pediatric endocrinologists. Demographic and clinical data including age, race, hemoglobin A_1c level, type of diabetes, and body mass index were also collected. Agreement rates between participants and physician assessment were compared. A level of agreement greater than 80% and a k coefficient greater than 0.61 were considered substantial.ResultsEighty-seven children and adolescents completed the study. Agreement rates for girls were greater than 80%. Agreement rates for boys were 76%. All k coefficients for boys and girls were greater than 0.61, corresponding to good agreement. However, peripubertal participants overestimated their sexual maturity rating almost half the time. The role of age, metabolic control (as measured by hemoglobin A_1c), race, type of diabetes, and body mass index did not influence a participant’s ability to accurately assess sexual maturity.ConclusionWhile useful in mid- to late-pubertal youth with diabetes, this self-assessment tool does not appear to be helpful in identifying the early stages of puberty. (Endocr Pract. 2008;14:840-845)     

Altered Volume,Morphology and Composition of the Pancreas in Type 2 Diabetes

ObjectiveAlthough impairment in pancreatic insulin secretion is known to precede the clinical diagnosis of type 2 diabetes by up to a decade, fasting blood glucose concentration only rises abnormally once the impairment reaches a critical threshold. Despite its centrality to the pathogenesis of type 2 diabetes, the pancreas is the least studied organ due to its inaccessible anatomical position. Previous ultrasound and CT studies have suggested a possible decrease in pancreatic volume in type 2 diabetes. However, ultrasound techniques are relatively insensitive while CT uses ionizing radiation, making these modalities unsuitable for precise, longitudinal studies designed to explore the underlying mechanisms of type 2 diabetes. Hence there is a need to develop a non-invasive, safe and precise method to quantitate pancreas volume.MethodsWe developed and applied magnetic resonance imaging at 3.0T to obtain balanced turbo field echo (BTFE) structural images of the pancreas, together with 3-point Dixon images to quantify pancreatic triglyceride content. Pancreas volume, morphology and triglyceride content was quantified in a group of 41 subjects with well-controlled type 2 diabetes (HbA_1c ≤ 7.6%) taking only metformin (duration of T2DM 5.7±0.7years), and a control group of 14 normal glucose tolerance subjects matched for age, weight and sex.ResultsThe mean pancreatic volume was found to be 33% less in type 2 diabetes than in normal glucose tolerant subjects (55.5±2.8 vs. 82.6±4.8cm³; p<0.0001). Pancreas volume was positively correlated with HOMA-β in the type 2 diabetes subjects (r = 0.31; p = 0.03) and controls (r = 0.46; p = 0.05) considered separately; and in the whole population studied (r = 0.37; p = 0.003). In type 2 diabetes, the pancreas was typically involuted with a serrated border. Pancreatic triglyceride content was 23% greater (5.4±0.3 vs. 4.4±0.4%; p = 0.02) in the type 2 diabetes group.ConclusionThis study describes for the first time gross abnormalities of the pancreas in early type 2 diabetes and quantifies the decrease in pancreas size, the irregular morphology and increase in fat content.     

Sitagliptin Compared with Thiazolidinediones as a Third-Line Oral Antihyperglycemic Agent in Type 2 Diabetes Mellitus

ObjectiveTo compare sitagliptin and thiazolidinediones as third-line oral antihyperglycemic agents among ethnic minority patients with poorly controlled type 2 diabetes mellitus.MethodsIn an open-label, single-arm design, we treated type 2 diabetic patients who had suboptimal diabetes control on maximum tolerated dosages of metformin plus sulfonylureas with the addition of sitagliptin, 100 mg daily, and compared their responses with findings from a historical control group of similar patients treated with rosiglitazone, 8 mg daily, or pioglitazone, 45 mg daily, as their third-line oral agent. Patients were assessed bimonthly, and those who achieved hemoglobin A_1c levels less than 7.5% at 4 months continued through 1 year of follow-up.Results:One hundred eight patients were treated with sitagliptin, and 104 patients constituted the historical control group treated with rosiglitazone or pioglitazone. At baseline, sitagliptinand thiazolidinedione-treated patients had identical hemoglobin A_1c levels (mean ± SD) (9.4 ± 1.8% and 9.4 ± 1.9%, respectively) and similar known diabetes duration (6.7 ± 5.0 years and 7.6 ± 5.8 years, respectively). Hemoglobin A_1c was reduced in both groups at 4 months (P < .001), but the reduction was greater with thiazolidinediones than with sitagliptin (-2.0 ± 1.7% vs -1.3 ± 1.8%; P = .006), as was the proportion of patients achieving a hemoglobin A_1c level less than 7.5% (62% vs 46%; P = .026). Of all patients achieving a hemoglobin A_1c level less than 7.5% at 4 months, the same proportions in each group sustained their hemoglobin A_1c level less than 7.5% by 12 months (59% vs 58%). Sitagliptin was well tolerated.ConclusionsAmong ethnic minority patients with poorly controlled type 2 diabetes while taking maximum tolerated dosages of metformin and sulfonylureas, thirdline add-on therapy with a thiazolidinedione controlled hyperglycemia more effectively than sitagliptin after 4 months. (Endocr Pract. 2011;17:691-698)