Value of glycaemic control in diabetes

Full text: Several Lancet publications have questioned the value of glycaemic control in diabetic patients. For example, in their Comment (Sept 29, p 1103),1 John Cleland and Stephen Atkin state that “Improved glycaemic control is not a surrogate for effective care of patients who have diabetes”, and Victor Montori and colleagues (p 1104)2 claim that “HbA1c loses its validity as a surrogate marker when patients have a constellation of metabolic abnormalities”. We are concerned that the reaction against “glucocentricity” in the field of diabetes has gone too far. Even the UK's National Prescribing Centre website, carrying the National Health Service logo, includes comments that undermine the value of glycaemic control. For example, referring to the United Kingdom Prospective Diabetes Study (UKPDS), this site states that “Compared with ‘conventional control’ there was no benefit from tight control of blood glucose with sulphonylureas or insulin with regard to total mortality, diabetes-related death, macrovascular outcomes or microvascular outcomes, including all the most serious ones such as blindness or kidney failure”.3 It is well established that better glycaemic control reduces long-term microvascular complications in type 1 and type 2 diabetes.4 In type 2 diabetes, the UKPDS reported that a composite microvascular endpoint (retinopathy requiring photocoagulation, vitreous haemorrhage, and fatal or non-fatal renal failure) was reduced by 25% in patients randomised to intensive glucose control (p=0·0099).4 To imply that these are not patient-relevant outcomes is to distort the evidence. Many studies have also found that improved glycaemic control reduces macrovascular complications.5 Do not be misled: glycaemic control remains a crucial component in the care of people with diabetes. The authors have received research support and undertaken ad hoc consultancies and speaker engagements for several pharmaceutical companies.

Inhaled human insulin (Exubera®):clinical profile and patient considerations

Inhaled human insulin (Exubera®) is a rapid-acting regular human insulin administered by oral inhalation before meals. It provides a non-invasive alternative to multiple subcutaneous injections for the treatment of hyperglycemia in adult patients with type 1 and type 2 diabetes. Compared with subcutaneous rapid-acting insulin analogs, Exubera provides equivalent HbA1c control. As a monotherapy or in combination with oral agents, Exubera also provides greater glycemic control than oral agents alone, at least in patients with high levels of HbA1c. Exubera demonstrates improved patient satisfaction compared with subcutaneous insulin or oral agents alone. When offered as a treatment option together with standard treatments in uncontrolled patients naive to insulin, Exubera increases acceptance of insulin therapy three-fold compared with patients offered standard regimens only. Exubera is well tolerated in comparison to subcutaneous insulin, with a similar incidence of mild to moderate hypoglycemia. Although cough is a common adverse effect early in therapy, this leads to treatment discontinuations in less than 1% of patients. Despite an increased incidence of insulin antibodies compared with subcutaneous administration, and a consistent but minor impact on pulmonary function, long-term safety data of up to 4 years continue to support the safety profile of Exubera.

A double-blind randomized study comparing the effects of continuing or not continuing rosiglitazone + metformin therapy when starting insulin therapy in people with type 2 diabetes

Aims: To compare the efficacy and safety of either continuing or discontinuing rosiglitazone + metformin fixed-dose combination when starting insulin therapy in people with Type 2 diabetes inadequately controlled on oral therapy. Methods: In this 24-week double-blind study, 324 individuals with Type 2 diabetes inadequately controlled on maximum dose rosiglitazone + metformin therapy were randomly assigned to twice-daily premix insulin therapy (target pre-breakfast and pre-evening meal glucose ≤ 6.5 mmol/l) in addition to either rosiglitazone + metformin (8/2000 mg) or placebo. Results: Insulin dose at week 24 was significantly lower with rosiglitazone + metformin (33.5 ± 1.5 U/day, mean ± se) compared with placebo [59.0 ± 3.0 U/day; model-adjusted difference -26.6 (95% CI -37.7, -15,5) U/day, P < 0.001]. Despite this, there was greater improvement in glycaemic control [HbA 1c rosiglitazone + metformin vs. placebo 6.8 ± 0.1 vs. 7.5 ± 0.1%; difference -0.7 (-0.8, -0.5)%, P < 0.001] and more individuals achieved glycaemic targets (HbA1c < 7.0% 70 vs. 34%, P < 0.001). The proportion of individuals reporting at least one hypoglycaemic event during the last 12 weeks of treatment was similar in the two groups (rosiglitazone + metformin vs. placebo 25 vs. 27%). People receiving rosiglitazone + metformin in addition to insulin reported greater treatment satisfaction than those receiving insulin alone. Both treatment regimens were well tolerated but more participants had oedema [12 (7%) vs. 4 (3%)] and there was more weight gain [3.7 vs. 2.6 kg; difference 1.1 (0.2, 2.1) kg, P = 0.02] with rosiglitazone + metformin. Conclusions: Addition of insulin to rosiglitazone + metformin enabled more people to reach glycaemic targets with less insulin, and was generally well tolerated. © 2007 The Authors.

Avandamet:Combined metformin-rosiglitazone treatment for insulin resistance in type 2 diabetes

Insulin resistance is a major endocrinopathy underlying the development of hyperglycaemia and cardiovascular disease in type 2 diabetes. Metformin (a biguanide) and rosiglitazone (a thiazolidinedione) counter insulin resistance, acting by different cellular mechanisms. The two agents can be used in combination to achieve additive glucose-lowering efficacy in the treatment of type 2 diabetes, without stimulating insulin secretion and without causing hypoglycaemia. Both agents also reduce a range of atherothrombotic factors and markers, indicating a lower cardiovascular risk. Early intervention with metformin is already known to reduce myocardial infarction and increase survival in overweight type 2 patients. Recently, a single-tablet combination of metformin and rosiglitazone, Avandamet, has become available. Avandamet is suitable for type 2-diabetic patients who are inadequately controlled by monotherapy with metformin or rosiglitazone. Patients already receiving separate tablets of metformin and rosiglitazone may switch to the single-tablet combination for convenience. Also, early introduction of the combination before maximal titration of one agent can reduce side effects. Use of Avandamet requires attention to the precautions for both metformin and rosiglitazone, especially renal, cardiac and hepatic competence. In summary, Avandamet is a single-tablet metformin-rosiglitazone combination that doubly targets insulin resistance as therapy for hyperglycaemia and vascular risk in type 2 diabetes. © 2004 Blackwell Publishing Ltd.

Glucosamine-induced insulin resistance in L6 muscle cells

Background: Glucosamine increases flux through the hexosamine pathway, causing insulin resistance and disturbances similar to diabetic glucose toxicity. Aim: This study examines the effect of glucosamine on glucose uptake by cultured L6 muscle cells as a model of insulin resistance. Methods: Glucose uptake by L6 myotubes was measured using the non-metabolized glucose analogue 2-deoxy-D-glucose after incubation with glucosamine for 4 and 24 h, with and without insulin and several other agents (metformin, peroxovanadium and D-pinitol) that improve glucose uptake in diabetic states. Results: After 4 h, high concentrations of glucosamine (5 × 10-3 and 10-2 M) reduced basal and insulin-stimulated glucose uptake by up to 50%. After 24 h, the effect of insulin was completely abolished by 10-2 M glucosamine and reduced over 50% by 5 × 10-3 M glucosamine. Lower concentrations of glucosamine did not significantly alter glucose uptake. The effect of glucosamine could not be attributed to cytotoxicity assessed by the Trypan Blue test. Metformin, peroxovanadium and D-pinitol, each of which increased glucose uptake by L6 cells, did not prevent the decrease in glucose uptake with glucosamine. Conclusion: Glucosamine decreased insulin-stimulated glucose uptake by L6 muscle cells, providing a potential model of insulin resistance with similarities to glucose toxicity. Insulin resistance induced by glucosamine was not reversed by three agents (metformin, peroxovanadium and D-pinitol) known to enhance or partially mimic the effects of insulin. © 2004 Blackwell Publishing Ltd.

GIP(Lys16PAL) and GIP(LyS37PAL):novel long-acting acylated analogues of glucose-dependent insulinotropic polypeptide with improved antidiabetic potentia

Glucose-dependent insulinotropic polypeptide (GIP) is a physiological insulin releasing peptide. We have developed two novel fatty acid derivatized GIP analogues, which bind to serum albumin and demonstrate enhanced duration of action in vivo. GIP(Lys16PAL) and GIP(Lys37PAL) were resistant to dipeptidyl peptidase IV (DPP IV) degradation. In vitro studies demonstrated that GIP analogues retained their ability to activate the GIP receptor through production of cAMP and to stimulate insulin secretion. Intraperitoneal administration of GIP analogues to obese diabetic (ob/ob) mice significantly decreased the glycemic excursion and elicited increased and prolonged insulin responses compared to native GIP. A protracted glucose-lowering effect was observed 24 h following GIP(Lys37PAL) administration. Once a day injection for 14 days decreased nonfasting glucose, improved glucose tolerance, and enhanced the insulin response to glucose. These data demonstrate that fatty acid derivatized GIP peptides represent a novel class of long-acting stable GIP analogues for therapy of type 2 diabetes. © 2006 American Chemical Society.

Laparoscopic greater curvature plication in morbidly obese women with type 2 diabetes:effects on glucose homeostasis, postprandial triglyceridemia and selected gut hormones

Background: Laparoscopic greater curvature plication (LGCP) is an emerging bariatric procedure that reduces the gastric volume without implantable devices or gastrectomy. The aim of this study was to explore changes in glucose homeostasis, postprandial triglyceridemia, and meal-stimulated secretion of selected gut hormones [glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), ghrelin, and obestatin] in patients with type 2 diabetes mellitus (T2DM) at 1 and 6 months after the procedure. Methods: Thirteen morbidly obese T2DM women (mean age, 53.2 ± 8.76 years; body mass index, 40.1 ± 4.59 kg/m2) were prospectively investigated before the LGCP and at 1- and 6-month follow-up. At these time points, all study patients underwent a standardized liquid mixed-meal test, and blood was sampled for assessment of plasma levels of glucose, insulin, C-peptide, triglycerides, GIP, GLP-1, ghrelin, and obestatin. Results: All patients had significant weight loss both at 1 and 6 months after the LGCP (p≤0.002), with mean percent excess weight loss (%EWL) reaching 29.7 ;plusmn2.9 % at the 6-month follow-up. Fasting hyperglycemia and hyperinsulinemia improved significantly at 6 months after the LGCP (p<0.05), with parallel improvement in insulin sensitivity and HbA1c levels (p<0.0001). Meal-induced glucose plasma levels were significantly lower at 6 months after the LGCP (p<0.0001), and postprandial triglyceridemia was also ameliorated at the 6-month follow-up (p<0.001). Postprandial GIP plasma levels were significantly increased both at 1 and 6 months after the LGCP (p<0.0001), whereas the overall meal-induced GLP-1 response was not significantly changed after the procedure (p ;gt0.05). Postprandial ghrelin plasma levels decreased at 1 and 6 months after the LGCP (p<0.0001) with no significant changes in circulating obestatin levels. Conclusion: During the initial 6-month postoperative period, LGCP induces significant weight loss and improves the metabolic profile of morbidly obese T2DM patients, while it also decreases circulating postprandial ghrelin levels and increases the meal-induced GIP response. © 2013 Springer Science+Business Media New York.

Insulin therapy in people with type 2 diabetes:opportunities and challenges?

Given the continued interest in defining the optimal management of individuals with type 2 diabetes, the Editor of Diabetes Care convened a working party of diabetes specialists to examine this topic in the context of insulin therapy. This was prompted by recent new evidence on the use of insulin in such people. The group was aware of evidence that the benefits of insulin therapy are still usually offered late, and thus the aim of the discussion was how to define the optimal timing and basis for decisions regarding insulin and to apply these concepts in practice. It was noted that recent evidence had built upon that of the previous decades, together confirming the benefits and safety of insulin therapy, albeit with concerns about the potential for hypoglycemia and gain in body weight. Insulin offers a unique ability to control hyperglycemia, being used from the time of diagnosis in some circumstances, when metabolic control is disturbed by medical illness, procedures, or therapy, as well as in the longer term in ambulatory care. For those previously starting insulin, various other forms of therapy can be added later, which offer complementary effects appropriate to individual needs. Here we review current evidence and circumstances in which insulin can be used, consider individualized choices of alternatives and combination regimens, and offer some guidance on personalized targets and tactics for glycemic control in type 2 diabetes. © 2014 by the American Diabetes Association.

The association between glycated haemoglobin levels and P100 visual evoked potentials in diabetes mellitus

Diabetes mellitus (DM) is a metabolic disorder which is characterised by hyperglycaemia resulting from defects in insulin secretion, insulin action or both. The long-term specific effects of DM include the development of retinopathy, nephropathy and neuropathy. Cardiac disease, peripheral arterial and cerebrovascular disease are also known to be linked with DM. Type 1 diabetes mellitus (T1DM) accounts for approximately 10% of all individuals with DM, and insulin therapy is the only available treatment. Type 2 diabetes mellitus (T2DM) accounts for 90% of all individuals with DM. Diet, exercise, oral hypoglycaemic agents and occasionally exogenous insulin are used to manage T2DM. The diagnosis of DM is made where the glycated haemoglobin (HbA1c) percentage is greater than 6.5%. Pattern-reversal visual evoked potential (PVEP) testing is an objective means of evaluating impulse conduction along the central nervous pathways. Increased peak time of the visual P100 waveform is an expression of structural damage at the level of myelinated optic nerve fibres. This was an observational cross sectional study. The participants were grouped into two phases. Phase 1, the control group, consisted of 30 healthy non-diabetic participants. Phase 2 comprised of 104 diabetic participants of whom 52 had an HbA1c greater than 10% (poorly controlled DM) and 52 whose HbA1c was 10% and less (moderately controlled DM). The aim of this study was to firstly observe the possible association between glycated haemoglobin levels and P100 peak time of pattern-reversal visual evoked potentials (PVEPs) in DM. Secondly, to assess whether the central nervous system (CNS) and in particular visual function is affected by type and/or duration of DM. The cut-off values to define P100 peak time delay was calculated as the mean P100 peak time plus 2.5 X standard deviations as measured for the non-diabetic control group, and were 110.64 ms for the right eye. The proportion of delayed P100 peak time amounted to 38.5% for both diabetic groups, thus the poorly controlled group (HbA1c > 10%) did not pose an increased risk for delayed P100 peak time, relative to the moderately controlled group (HbA1c ≤ 10%). The P100 PVEP results for this study, do however, reflect significant delay (p < 0.001) of the DM group as compared to the non-diabetic group; thus, subclincal neuropathy of the CNS occurs in 38.5% of cases. The duration of DM and type of DM had no influence on the P100 peak time measurements.

Risk factors of coronary heart disease and correlates of type 2 diabetes among Cuban Americans

Cuban Americans, a minority Hispanic subgroup, have a high prevalence of type 2 diabetes. Persons with diabetes experience a higher rate of coronary heart disease (CHD) compared to those without diabetes. The objectives of the National Institute of Diabetes and Digestive and Kidney Disease (NIDDK) are to investigate the risk factors of CHD and the etiology of diabetes among diabetics of minority ethnic populations. No information is available on the etiology of CHD risks for Cuban Americans. ^ This cross-sectional study compared Cuban Americans with (N = 79) and without (N = 80) type 2 diabetes residing in South Florida. Data on risk factors of CHD and type 2 diabetes were collected using sociodemographics, smoking habit, Rose Angina, Modifiable Activity, and Willet's food frequency questionnaires. Anthropometrics and blood pressure (BP) were recorded. Glucose, glycated hemoglobin, lipid profile, homocysteine, and C-reactive protein were assessed in fasting blood. ^ Diabetics reported a significantly higher rate of angina symptoms than non-diabetics (P = 0.008). After adjusting for age and gender, diabetics had significantly (P < 0.001) larger waist circumference and higher systolic BP than non-diabetics. There was no significant difference in major nutrient intakes between the groups. One quarter of subjects, both diabetics and non-diabetics, exceeded the intake of percent calories from total fat and almost 60% had cholesterol intake >200 mg/d and more than 60% had fiber intake <20 gm/d. The pattern of physical activity did not differ between groups though, it was much below the recommended level. After adjusting for age and gender, diabetics had significantly (P < 0.001) higher levels of blood glucose, glycated hemoglobin, triglycerides, and homocysteine than non-diabetics. In contrast, diabetics had significantly (P < 0.01) lower levels of high-density lipoprotein cholesterol (HDL-C). ^ Multivariate logistic regression analyses showed that increasing age, male gender, large waist circumference, lack of acculturation, and high levels of triglycerides were independent risk factors of type 2 diabetes. In contrast, moderate alcohol consumption conferred protection against diabetes. ^ The study identified several risk factors of CHD and diabetes among Cuban Americans. Health care providers are encouraged to practice ethno-specific preventive measures to lower the burden of CHD and diabetes in Cuban Americans. ^

Risk factors for type 2 diabetes mellitus and cardiovascular diseases in Hispanic adolescents

This cross-sectional study evaluated risk factors (RF) for type 2 diabetes (T2DM) and cardiovascular diseases (CVD) in 100 Hispanic adolescents(50 overweight, 50 non-overweight) aged 12-16 years, and their associations with body mass index (BMI), diet, physical activity (PA), gender, and birth weight (BW). The RF studied were fasting plasma glucose (FPG), insulin sensitivity (IS), total cholesterol (TC), triacylglycerols (TG), low-density lipoprotein cholesterol (LDL), high-density lipoprotein cholesterol (HDL), acanthosis nigricans (AN), and blood pressure (BP). Dietary intakes were assessed using the Block Kids Questionnaire, fat-related intake behavior (FB) using the Fat-Related Diet Habits Questionnaire, and PA using the Modifiable Activity Questionnaire for Adolescents. Blood was collected after an overnight fast of 12 hours. All statistical analyses used SPSS 14.0. Overweight adolescents had presence of AN, higher BP, TC, TG, and LDL, and lower IS, ps < .001, as compared to non-overweight adolescents. Overweight adolescents were more likely to have 1 and 2 RF for T2DM and CVD as compared to having 0, ps < .001, and 2 RF as compared to having 1, p =.033. Adolescents with kilocalorie (Kcal) intake above requirements for age gender, and PA level were 4.6 times more likely to be overweight, p = .005. Overweight adolescents had worse FB, p = .011, and lower PA, p < .001. Adolescents with worse FB had higher BP, p = .016. Fiber below recommendations (14g/1,000 Kcal) was associated with being overweight, p = .012, and lower IS, p = .040. Adolescents with higher BW had higher FPG, p = .013. Our findings point to an association between being overweight and RF for T2DM and CVD, suggesting that overweight during adolescence may have serious health consequences for Hispanic adolescents. Also, our results indicate that Hispanic overweight adolescents eat more Kcal and less fiber than required, have worst FB, and less PA levels than their non-overweight counterparts. In addition, high BW and dietary habits of Hispanic adolescents, such as low fiber and FB, increase their risk for T2DM and CVD. We conclude that BMI can serve as a useful tool to identify Hispanic adolescents at risk for T2DM and CVD.

Medical advice and diabetes self-management reported by Mexican-American, Black- and White-non-Hispanic adults across the United States

Background Diabetes has reached epidemic proportions in the United States, particularly among minorities, and if improperly managed can lead to medical complications and death. Healthcare providers play vital roles in communicating standards of care, which include guidance on diabetes self-management. The background of the client may play a role in the patient-provider communication process. The aim of this study was to determine the association between medical advice and diabetes self care management behaviors for a nationally representative sample of adults with diabetes. Moreover, we sought to establish whether or not race/ethnicity was a modifier for reported medical advice received and diabetes self-management behaviors. Methods We analyzed data from 654 adults aged 21 years and over with diagnosed diabetes [130 Mexican-Americans; 224 Black non-Hispanics; and, 300 White non-Hispanics] and an additional 161 with 'undiagnosed diabetes' [N = 815(171 MA, 281 BNH and 364 WNH)] who participated in the National Health and Nutrition Examination Survey (NHANES) 2007-2008. Logistic regression models were used to evaluate whether medical advice to engage in particular self-management behaviors (reduce fat or calories, increase physical activity or exercise, and control or lose weight) predicted actually engaging in the particular behavior and whether the impact of medical advice on engaging in the behavior differed by race/ethnicity. Additional analyses examined whether these relationships were maintained when other factors potentially related to engaging in diabetes self management such as participants' diabetes education, sociodemographics and physical characteristics were controlled. Sample weights were used to account for the complex sample design. Results Although medical advice to the patient is considered a standard of care for diabetes, approximately one-third of the sample reported not receiving dietary, weight management, or physical activity self-management advice. Participants who reported being given medical advice for each specific diabetes self-management behaviors were 4-8 times more likely to report performing the corresponding behaviors, independent of race. These results supported the ecological model with certain caveats. Conclusions Providing standard medical advice appears to lead to diabetes self-management behaviors as reported by adults across the United States. Moreover, it does not appear that race/ethnicity influenced reporting performance of the standard diabetes self-management behavior. Longitudinal studies evaluating patient-provider communication, medical advice and diabetes self-management behaviors are needed to clarify our findings.

The association of depression and perceived stress with beta cell function between African and Haitian Americans with and without type 2 diabetes

Background: Diabetes and diabetes-related complications are major causes of morbidity and mortality in the United States. Depressive symptoms and perceived stress have been identified as possible risk factors for beta cell dysfunction and diabetes. The purpose of this study was to assess associations between depression symptoms and perceived stress with beta cell function between African and Haitian Americans with and without type 2 diabetes. Participants and Methods: Informed consent and data were available for 462 participants (231 African Americans and 231 Haitian Americans) for this cross-sectional study. A demographic questionnaire developed by the Primary Investigator was used to collect information regarding age, gender, smoking, and ethnicity. Diabetes status was determined by self-report and confirmed by fasting blood glucose. Anthropometrics (weight, and height and waist circumference) and vital signs (blood pressure) were taken. Blood samples were drawn after 8 10 hours over-night fasting to measure lipid panel, fasting plasma glucose and serum insulin concentrations. The homeostatic model assessment, version 2 (HOMA2) computer model was used to calculate beta cell function. Depression was assessed using the Beck Depression Inventory-II (BDI-II) and stress levels were assessed using the Perceived Stress Scale (PSS). Results: Moderate to severe depressive symptoms were more likely for persons with diabetes (p = 0.030). There were no differences in perceived stress between ethnicity and diabetes status (p = 0.283). General linear models for participants with and without type 2 diabetes using beta cell function as the dependent variable showed no association with depressive symptoms and perceived stress; however, Haitian Americans had significantly lower beta cell function than African Americans both with and without diabetes and adjusting for age, gender, waist circumference and smoking. Further research is needed to compare these risk factors in other race/ethnic groups.

Ethnic Differences in Insulin Resistance, Adiponectin Levels and Abdominal Obesity: Haitian Americans and African Americans, with and without Type 2 Diabetes Mellitus

Background: Metabolic outcomes of obesity and its associated disorders may not be equivalent across ethnicity and diabetes status. Aim: In this paper, we examined the association of abdominal obesity, by ethnicity and diabetes status, for indicators of glucose metabolism in Blacks. Methods: A cross sectional study was conducted in Haitian Americans (n= 186) and African Americans (n= 148) with and without type 2 diabetes mellitus (T2DM). Student’s t-test and Chi-squared test were used to assess differences in mean and proportion values between ethnicities with and without type 2 diabetes mellitus. Relationship between insulin resistance, ethnicity, diabetes status, abdominal obesity, and adiponectin levels were analyzed by analysis of covariance while controlling for confounding variables. Results:Haitian American participants were older (P = .032), had higher fasting plasma glucose (P = .036), and A1C (P = .016), but had lower levels of Hs-CRP (P < .001), insulin and HOMA2-IR and lower abdominal obesity (P = .030), than African Americans. Haitian Americans had significantly lower HOMA2-IR (P = .008) than African Americans when comparing both ethnicities with T2DM, high abdominal obesity, and adiponectin levels lower than the median ( Conclusion: The clinical significance of observed differences in insulin resistance, abdominal obesity, and adiponectin levels between Haitian Americans and African Americans could assist in forming public health policies that are ethnic specific.