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Basal-prandial insulin therapy: Scientific concept review and application.

The majority of patients with type 2 diabetes mellitus (T2DM) eventually require the addition of basal insulin to existing oral therapy to achieve the glycemic goals set forth by the American Diabetes Association (A1C, <7.0%). In many patients with T2DM, insulin is the only option for achieving glycemic control and may be used successfully to attain glycemic targets in regimens that combine basal insulin with oral antidiabetic agents, or in regimens that combine basal insulin with mealtime (prandial) insulin. Basal-prandial insulin regimens that use a long-acting insulin analogue to control the fasting plasma glucose level and a short-acting insulin analogue for post-meal glucose excursions replace insulin in a manner that most closely approximates normal physiologic patterns. The current body of evidence demonstrates that such regimens will prove to be the optimal strategy for achieving glycemic control in patients with T2DM who require both basal and prandial insulin replacement. Here, we review current findings in the published literature on the efficacy of basal-prandial insulin, with a focus on practical information that might help to provide an evidence-based guide for progressing to basal-prandial insulin therapy in appropriate patients with T2DM.

Basal Metabolism↗

Renal protection in diabetic patients: benefits of a first-line combination of perindopril-indapamide (Preterax).

Type 2 diabetes mellitus (T2DM) is often accompanied by high blood pressure (BP) and the clustering of several cardiovascular risk factors, and is the most frequent cause of end-stage renal disease. The stages of development of overt nephropathy in T2DM patients range from an initial alteration in renal function with an increased GFR, followed by the development of microalbuminuria and macroalbuminuria or proteinuria, featuring an established diabetic nephropathy, which eventually progresses to end-stage renal disease. Early intervention is needed to prevent the development of diabetic nephropathy and requires effective control of the different risk factors, and in particular high BP. In the initial stages of the disease, strict BP control is crucial to prevent the development of initial renal and vascular damage. Adequate BP control is particularly difficult in T2DM patients and in most cases requires the use of combination therapy. Preterax, a fixed-dose combination of perindopril 2 mg and indapamide 0.625 mg, allows BP to be significantly reduced compared with conventional strategies; this combination can be uptitrated to BiPreterax when further BP control is needed. In the PREMIER study performed in T2DM over 12 months, the perindopril/indapamide combination brought about, in addition to excellent BP control, a significant reduction in urinary albumin excretion, compared with monotherapy with enalapril. In more advanced degrees of renal damage, higher doses of the fixed combination have to be considered. The pharmacological basis of the renoprotective effect of perindopril/indapamide is the demonstration that this combination prevented nephropathy as well as proteinuria in obese Zucker rats, independently of BP control. Strict BP control from the initial stages of nephropathy together with inhibition of the renin-angiotensin system is mandatory to prevent albuminuria. The fixed combination of perindopril/indapamide can greatly help clinicians in achieving the above goals, using Preterax in the early and BiPreterax in the late stages of nephropathy.

Albuminuria↗

The Association Between NT-Pro BNP, Nephropathy and Endothelial Dysfunction in Patients With Type 2 Diabetes Mellitus.

BACKGROUND: N-terminal pro-B-type natriuretic peptide (NT-Pro BNP) is an established biomarker of heart failure and has been recommended for cardiovascular risk stratification in type 2 diabetes mellitus (T2DM). However, its relationship with diabetic nephropathy and endothelial dysfunction across varying stages of kidney impairment remains unclear. This study examined the associations of NT-Pro BNP, renal impairment, albuminuria and endothelial dysfunction in patients with T2DM without overt heart failure. METHODS: A comparative cross-sectional study was conducted among 192 adults with T2DM. Participants were stratified by KDIGO eGFR groups (&#x2265;&#x2009;90, 60-89, 30-59&#x2009;mL/min/1.73m2). NT-Pro BNP was considered abnormal at a cut-off of &#x2265;&#x2009;125&#x2009;pg/mL. Albuminuria was categorized using the urinary albumin-to-creatinine ratio (uACR). Endothelial function was assessed by brachial artery flow-mediated dilatation (FMD). Logistic regression analysis was performed to identify independent factors of elevated NT-Pro BNP, with p-values <&#x2009;0.05 considered statistically significant. RESULTS: NT-Pro BNP levels were significantly higher in the lower eGFR groups compared with normal eGFR (204.3 vs. 96.8 vs. 62.2&#x2009;pg/mL, p&#x2009;<&#x2009;0001). A weak but significant positive correlation was observed between NT-Pro BNP and uACR (r&#x2009;=&#x2009;0.31, p&#x2009;<&#x2009;0.001). However, no significant association was found between NT-Pro BNP and FMD (p&#x2009;=&#x2009;0.388). Following multivariable adjustments, older age (adjusted OR 1.14, 95% CI: 1.06-1.23, p&#x2009;<&#x2009;0.001), higher systolic blood pressure (adjusted OR 1.05, 95% CI: 1.02-1.08, p&#x2009;=&#x2009;0.010), lower eGFR (adjusted OR 0.97, 95% CI: 0.95-0.99, p&#x2009;=&#x2009;0.003) and beta-blocker use (adjusted OR 4.65, 95% CI: 1.61-13.45, p <&#x2009;0.001) were independently associated with elevated NT-Pro BNP. CONCLUSION: In patients with T2DM without overt heart failure, elevated NT-Pro BNP showed a statistically significant association with lower eGFR and higher albuminuria. Moderate to severe albuminuria becomes an independent factor for elevated NT-Pro BNP after adjustment excluding eGFR. The lack of association with endothelial dysfunction suggests that NT-Pro BNP may reflect different pathophysiological pathways. NT-Pro BNP may serve as a useful biomarker for early cardiovascular risk stratification and identification of individuals at risk of pre-heart failure in diabetic kidney disease.

NT&#x2010;Pro BNP↗

Insulin resistance, endocrine function and adipokines in type 2 diabetes patients at different glycaemic levels: potential impact for glucotoxicity in vivo.

OBJECTIVE: To evaluate the interplay between hyperglycaemia, insulin resistance, hormones and adipokines in patients with type 2 diabetes mellitus (T2DM). DESIGN AND METHODS: Ten patients with T2DM with good glycaemic control (G), 10 with poor control (P) and 10 nondiabetic control subjects (C) were matched for sex (M/F 6/4), age and body mass index. A hyperinsulinaemic, euglycaemic clamp was performed and cytokines and endocrine functions, including cortisol axis activity were assessed. RESULTS: Patients with diabetes were more insulin resistant than group C, and group P exhibited the highest degree of insulin resistance (P = 0.01, P vs C). Tumour necrosis factor (TNF)-alpha levels were elevated in patients with diabetes (P = 0.05) and group P had the highest levels of fasting serum cortisol (P = 0.05), nonesterified fatty acids (NEFA; P = 0.06) and C-reactive protein (CRP; P = 0.01). Adiponectin levels were lower in the P group. In partial correlation analyses, significant associations were found: glycaemic level (HbA1c) with insulin resistance, TNF-alpha, CRP and basal and ACTH-stimulated cortisol levels, insulin resistance with plasma NEFA, TNF-alpha and stimulated cortisol levels. CONCLUSION: Poor glycaemic control in patients with T2DM was associated with insulin resistance and with elevated TNF-alpha, CRP and basal as well as stimulated cortisol levels. Inflammatory mediators, e.g. TNF-alpha, may contribute to insulin resistance in hyperglycaemic patients with T2DM and this might be a partial explanation for glucotoxicity.

Adipose Tissue↗

Lipoprotein(a), type 2 diabetes and vascular risk in coronary patients.

BACKGROUND: Lipoprotein(a) [Lp(a)] is an important cardiovascular risk factor in the general population. However, prospective data on the vascular risk conferred by Lp(a) in patients with diabetes mellitus are scarce and controversial. It is not known whether the diabetic state affects the association of Lp(a) with vascular events among coronary patients. DESIGN: We measured Lp(a) in 587 consecutive patients undergoing coronary angiography for the evaluation of coronary artery disease. The incidence of vascular events was recorded over 4 years. RESULTS: At baseline, Lp(a) was significantly lower in patients with type 2 diabetes (T2DM) (n = 136) than in nondiabetic individuals (11 (0.8-30) mg dL(-1) vs. 16 (0.8-51) mg dL(-1); P = 0.025). Prospectively, Lp(a) was a strong and independent predictor of vascular events in nondiabetic patients (standardized adjusted hazard ratio (HR) = 1.461 (1.121-1.904); P = 0.005), but not in patients with T2DM [HR = 0.812 (0.539-1.223); P = 0.320]. An interaction term diabetes x Lp(a) was significant (P = 0.008), indicating that Lp(a) was a significantly stronger predictor of vascular events in nondiabetic patients than in patients with T2DM. CONCLUSIONS: Lp(a) in diabetic coronary patients is low and not associated with the incidence of vascular events. Although measurement of Lp(a) provides useful information in nondiabetic coronary patients, it is of little value in coronary patients with T2DM.

Aged↗

Diabetes prevention: is there more to it than lifestyle changes?

Over the past years, there has been an explosive increase in the prevalence of type 2 diabetes (T2DM) and this is expected to continue, entailing associated morbidity and mortality. An increasing number of studies explore the different ways T2DM could be prevented. On-going lifestyle modifications need to be addressed. High-risk patients should be given counselling on weight loss, possibly using a low glycaemic index diet, with a target of around 7-10% over 6-12 months, as well as instruction for increasing physical activity to around 150 min of physical exercise weekly (NNT = 4-8). Moderate alcohol consumption and coffee consumption may also be of benefit (NNT = 89 and 66, respectively). Metformin (NNT = 14), acarbose (NNT = 11) and troglitazone (NNT = 6) have been shown to prevent/delay T2DM and angiotensin-converting enzyme (ACE) inhibitors and statins appear to have an adjunctive role (NNT = 42 and 112, respectively). Trials with orlistat and bariatric surgery have also prevented T2DM (NNT = 36 and 6, respectively), and forthcoming treatment with GLP1 mimetics appears promising. Diabetes prevention studies should help create well-defined strategies for screening and treating high-risk populations in the real world, as prevention is our only chance to alleviate the ever growing burden of diabetes mellitus in the world.

Diabetes Mellitus, Type 2↗

Efficacy and safety of ezetimibe co-administered with simvastatin in thiazolidinedione-treated type 2 diabetic patients.

AIM: In patients with type 2 diabetes mellitus (T2DM), combination therapy is usually required to optimize glucose metabolism as well as to help patients achieve aggressive targets for low-density lipoprotein cholesterol (LDL-C) and other lipid parameters associated with cardiovascular risk. The thiazolidinediones (TZDs) are increasingly being used for both their blood glucose-lowering properties and their modest beneficial effects on triglycerides (TG) and high-density lipoprotein cholesterol (HDL-C). Ezetimibe, an intestinal cholesterol absorption inhibitor, has a mechanism of action that differs from that of statins, which inhibit hepatic cholesterol synthesis. We compared the lipid-modifying efficacy and safety of adding ezetimibe to simvastatin, vs. doubling the dose of simvastatin, in TZD-treated T2DM patients. METHODS: This was a randomized, double-blind, parallel group, multicentre study in T2DM patients, 30-75 years of age, who had been on a stable dose of a TZD for at least 3 months and had LDL-C > 2.6 mmol/l (100 mg/dl) prior to study entry. Other antidiabetic medications were also allowed. Following 6 weeks of open-label simvastatin 20 mg/day, patients were randomized to the addition of either blinded ezetimibe 10 mg/day (n = 104) or an additional blinded simvastatin 20 mg/day (total simvastatin 40 mg/day; n = 110) for 24 weeks. Patients were stratified according to TZD type and dose (pioglitazone 15-30 vs. 45 mg/day; rosiglitazone 2-4 vs. 8 mg/day). RESULTS: LDL-C was reduced more (p < 0.001) by adding ezetimibe 10 mg to simvastatin 20 mg (-20.8%) than by doubling the dose of simvastatin to 40 mg (-0.3%). Ezetimibe plus simvastatin 20 mg also produced significant incremental reductions in non-HDL-C (p < 0.001), very low-density lipoprotein cholesterol (p < 0.05) and apolipoprotein B (p < 0.001) relative to simvastatin 40 mg. There were no differences between the groups with respect to changes in TG and HDL-C levels, and both treatments were well tolerated. CONCLUSIONS: Co-administration of ezetimibe with simvastatin, a dual inhibition treatment strategy targeting both cholesterol synthesis and absorption, is well tolerated and provides greater LDL-C-lowering efficacy than increasing the dose of simvastatin in T2DM patients taking TZDs.

Adult↗

Relative androgen deficiency in relation to obesity and metabolic status in older men.

BACKGROUND: Although androgen deficiency in men has been linked with obesity and the metabolic syndrome, whether it predisposes to, or is a consequence of, type 2 diabetes mellitus (T2DM) is still unclear. OBJECTIVE: To determine the relationship between plasma androgen levels, obesity, metabolic status and T2DM in men of 70 years or older. DESIGN AND METHODS: A sample of 195 men from the Australian Longitudinal Study of Ageing with a mean age of 76.2 +/- 0.3 years were followed up for 8 years. Total testosterone (TT), fasting plasma glucose (FPG), urate, serum creatinine, total cholesterol (TC), HDL cholesterol (HDL-C), LDL cholesterol (LDL-C), triglycerides (TG), blood pressure (BP), body mass index (BMI), waist circumference (WC) and diabetic status were assessed at baseline. Self-reported diabetic status was obtained after 8 years. Metabolic syndrome was diagnosed based on the Third National Cholesterol Education Program Adult Treatment Panel clinical criteria. RESULTS: TT levels were lower in diabetic men compared with non-diabetic men (12.1 +/- 0.7 vs. 14.2 +/- 0.4 nmol/l, p = 0.026). TT levels in healthy, non-diabetic men over 80 years of age were lower (11.9 +/- 0.8 vs. 15.0 +/- 0.5 nmol/l, p = 0.002) than TT levels in those aged 70-79 years, inversely related to BMI (r = -0.26, p = 0.001), WC (r = -0.30, p < 0.001) and TG (r = -0.22, p = 0.005) and positively related to LDL-C (r = 0.25, p = 0.002). Men with the metabolic syndrome had significantly lower levels of TT and HDL-C, and higher values of BP, FPG, TG, BMI and WC, compared with those without. However, no significant difference in plasma TT levels was noted between men with incident T2Dm and healthy men. Stepwise linear regression analysis revealed that only LDL-C and WC related significantly to the variance of TT. Multiple logistic regression revealed FPG to be the only independent predictor of incident diabetes (odds ratio = 60.2, p = 0.003). CONCLUSIONS: Testosterone levels continue to decline even in healthy men over the age of 80 years. Although TT levels were inversely related to visceral obesity and several components of the metabolic syndrome, our data do not support a predictive or causative role for decreasing TT levels in the development of incident T2Dm. Androgen deficiency is consequent upon, rather than a cause of, poor metabolic status.

Aged↗

Effect of early addition of rosiglitazone to sulphonylurea therapy in older type 2 diabetes patients (>60 years): the Rosiglitazone Early vs. SULphonylurea Titration (RESULT) study.

AIM: To compare the efficacy, safety and tolerability of adding rosiglitazone (RSG) vs. sulphonylurea (SU) dose escalation in older type 2 diabetes mellitus (T2DM) patients inadequately controlled on SU therapy. METHODS: A total of 227 T2DM patients from 48 centres in the USA and Canada, aged > or =60 years, were randomized to receive RSG (4 mg) or placebo once daily in combination with glipizide 10 mg twice daily for 2 years in a double-blind, parallel-group study. Previous SU monotherapy was (1/4) to (1/2) maximum recommended dose for > or =2 months prior to screening with fasting plasma glucose (FPG) > or =7.0 and < or =13.9 mmol/l. Treatment options were individualized, and escalation of study medication was specifically defined. RESULTS: Disease progression (time to reach confirmed FPG > or =10 mmol/l while on maximum doses of both glipizide and study medication or placebo) was reported in 28.7% of patients uptitrating SU plus placebo compared with only 2.0% taking RSG and SU combination (p < 0.0001). RSG + SU significantly decreased HbA(1c), FPG, insulin resistance, plasma free fatty acids and medical care utilization and improved treatment satisfaction compared with uptitrated SU. CONCLUSIONS: Addition of RSG to SU in older T2DM patients significantly improved glycaemic control and reduced disease progression compared with uptitrated SU alone but without increasing hypoglycaemia. These benefits were associated with increased patient treatment satisfaction and reduced medical care utilization with regards to emergency room visits and length of hospitalization. Early addition of RSG is an effective treatment option for older T2DM patients inadequately controlled on submaximal SU monotherapy.

Age Factors↗

Prevalence and risk factors for stroke in Type 2 diabetic patients in Taiwan: a cross-sectional survey of a national sample by telephone interview.

AIMS: To determine the prevalence and risk factors for stroke in patients with Type 2 diabetes mellitus (T2DM) and the age-specific prevalence odds ratios (POR) in comparison with the general population in Taiwan. METHODS: A total of 16 994 T2DM patients were randomly selected for telephone interview from a group covered by the National Health Insurance programme. Lifetime prevalence of stroke was calculated and various risk factors were analysed. Age-specific POR was calculated using previously reported prevalence of stroke in the general population from a nationwide survey across Taiwan. Standardized prevalence and POR were also calculated using the 2000-2025 population of the World Health Organization. RESULTS: A total of 12 531 cases (73.7%) were successfully interviewed. Stroke prevalence was 7.5%. In multivariate logistic regression, independent predictors were: increasing age, male gender, lower body mass index, ex-smokers, hyperlipidaemia, systolic pressure (or diastolic pressure when systolic pressure was not adjusted), education level below high school, and living in eastern or southern Taiwan. When compared with the general population, POR for stroke in the age groups < 45, 45-54, 55-64 and > or = 65 years were 82.29 (9.60, 705.57), 5.43 (2.33, 12.68), 3.73 (2.20, 6.33) and 2.14 (1.59, 2.89), respectively. The age-standardized prevalence of stroke was 2.3% in the diabetic patients and 0.6% in the general population. CONCLUSIONS: Stroke prevalence in Taiwanese T2DM is 7.5%. Diabetic patients have a higher risk of stroke than the general population, but the relative risk attenuates with age. Besides conventional atherosclerotic risk factors, stroke patients in Taiwan are characterized by lower body mass index, lower education level and residence in southern or eastern Taiwan. The negative association between body mass index and stroke in Taiwanese T2DM is in contrast to the generally accepted concept that obesity is a major risk factor as seen in most western countries.

Adult↗

The effect of obesity on glycaemic response to metformin or sulphonylureas in Type 2 diabetes.

AIMS: In treating Type 2 diabetes (T2DM), UK guidelines recommend metformin in obese and overweight patients, and either sulphonylureas or metformin in normal weight patients. Although other factors influence prescribing choice, a key objective in treating T2DM is to lower plasma glucose. There is little data on how glycaemic response to oral agents varies with body mass index (BMI). Therefore, we assessed current prescribing practice and effect of BMI on glycaemic response to sulphonylureas and metformin in a large population T2DM cohort. METHODS: BMI was determined in 3856 T2DM patients on sulphonylurea or metformin monotherapy in 2001-2002. Patients were identified from the Diabetes Audit and Research in Tayside, Scotland (DARTS) database. In a linear regression, the effect of BMI and other confounders on drug response was assessed in 2064 treatment-naïve patients commencing sulphonylureas or metformin between 1994 and 2002. RESULTS: In 2001-2002, metformin was more likely to be used in obese than non-obese patients: 13% normal weight, 33.6% overweight and 62.1% obese patients were treated with metformin. Glycaemic response to sulphonylureas was not influenced by BMI (P = 0.81). Metformin was more effective in lowering glucose in those with a lower BMI (r = -0.02, P = 0.02), although the clinical impact of this was small. The HbA(1c) reduction in non-obese patients was similar to that in obese patients (1.46% vs. 1.34%, P = 0.11). CONCLUSIONS: Glycaemic response to metformin in non-obese and obese patients is similar, suggesting that an individual's BMI should not influence the choice of oral agent. Given the non-glycaemia-related benefits of metformin, it should be used in more non-obese patients than is current practice in Tayside, Scotland.

Aged↗

The visfatin gene is associated with glucose and lipid metabolism in a Chinese population.

AIMS: Visfatin is a newly discovered adipokine found in abundance in visceral fat. It lowers plasma glucose in humans and mice. In this study, we explored the relationships between the plasma level of visfatin and genetic single nucleotide polymorphisms (SNPs) and Type 2 diabetes mellitus (T2DM) and anthropometric and metabolic parameters in Chinese subjects. METHODS: Oral glucose tolerance tests (OGTT) and biochemical assays for plasma insulin, lipid profiles and serum visfatin were performed in 241 newly diagnosed T2DM patients, subjects with impaired glucose regulation (IGR), and normal glucose tolerant subjects more than 40 years of age. Genotyping for three SNP loci: -1535C/T, rs2058539 and rs10953502 were performed using the allele-specific real-time PCR method. RESULTS: Visfatin levels were similar in T2DM patients, IGR and normal glucose tolerant subjects. However, visfatin levels were significantly lower in obese than normal-weight subjects (13.66 +/- 0.87 vs. 15.46 +/- 0.47 ng/ml, P = 0.03). There was suggestively significant correlation between visfatin level and body mass index (r = -0.17 P = 0.07) and waist-hip ratio (r = 0.16 P = 0.08) in male subjects, but not in female subjects. Allele and common haplotype frequencies of the three SNP loci were similar in T2DM patients, IGR and normal glucose tolerant subjects. However, significant associations were found between these three SNP loci and plasma glucose concentration at 0 and 120 min during OGTT, the area under the response curve for plasma glucose, and triglyceride and total cholesterol levels. CONCLUSIONS: Serum visfatin levels may be related to visceral obesity in men, and the visfatin gene may account for variation of glucose and lipid parameters in Chinese subjects.

Adult↗

Asymmetrical dimethylarginine is related to renal function, chronic inflammation and macroangiopathy in patients with Type 2 diabetes and albuminuria.

AIMS: Patients with Type 2 diabetes mellitus (T2DM) and micro- and macroalbuminuria are at increased cardiovascular risk. The endogenous nitric oxide synthase inhibitor asymmetrical dimethylarginine (ADMA) is increased in renal failure and could promote atherosclerosis. To determine the relationship between ADMA, renal albumin excretion rate (AER) and cardiovascular risk, we studied 103 T2DM patients. METHODS: ADMA, symmetrical dimethylarginine (SDMA) and L-arginine were determined by high-performance liquid chromatography in plasma from 36 normo-, 40 micro- and 27 macroalbuminuric patients with T2DM (age 64 +/- 11 years; 38 women) who had comparable age, sex and metabolic parameters. Forty-six patients had macrovascular disease (MVD). RESULTS: ADMA was significantly increased in patients with micro- and macroalbuminuria [median 0.61 (interquartile range 0.55-0.70) micromol/l and 0.62 (0.50-0.79) micromol/l, respectively] compared with those with normoalbuminuria [0.55 (0.48-0.63) micromol/l; both P < 0.05]. SDMA was elevated in micro- and macroalbuminuria [0.57 (0.42-0.80) micromol/l and 0.64 (0.50-0.96) micromol/l] compared with normoalbuminuric subjects [0.44 (0.37-0.53) micromol/l; both P < 0.01]. Patients with increased AER and MVD had higher ADMA and SDMA compared with those without MVD (both P < 0.001). L-arginine was comparable between all groups. ADMA correlated significantly with high-sensitivity C-reactive protein (hsCRP) and glomerular filtration rate (GFR) but not with the extent of albumin excretion, body mass index, fasting glucose, HbA(1c) or plasma lipids. CONCLUSIONS: Increased ADMA in T2DM patients with albuminuria is linked to cardiovascular disease and is associated with renal dysfunction and subclinical inflammation.

Aged↗

Common adiponectin gene variants show different effects on risk of cardiovascular disease and type 2 diabetes in European subjects.

Alterations in the secretion of adipokines may explain the link between obesity, type 2 diabetes (T2DM) and coronary artery disease (CAD). These conditions have been associated with variation in the adiponectin gene, although evidence for this relationship has been variable, with differences found even in similar samples. This study aims to clarify these inconsistencies by determining the impact of identified adiponectin gene (ADIPOQ) variants (-11391G>A,-1377C>G[promoter] and +45T>G[exon 2] and +276G>T[intron 2]) on the prospective risk of CAD and T2DM in healthy men, and on adverse metabolic markers, in myocardial infarct survivors and controls from different parts of Europe. The hazard ratio for cardiovascular disease varied across the -11391GG/GA/AA(p = 0.03) and -11371CC/CG/GG(p = 0.05) genotypes only. In contrast, only the +45T>G variant (3.80[1.76-8.24]) was associated with T2DM, while two haplotypes GCTT/GCGG (p < 0.05) and +276G>T(p = 0.01) increased risk in interaction with obesity. The variants were associated with a number of biomarkers in Southern but not Northern Europe (p = 0.01), despite no significant differences in allele or haplotype frequencies (p > 0.44). A risk haplotype could not be identified in either sample. Adiponectin gene variants are hence currently poor markers for the development of T2DM and CAD. Their influence on risk depends significantly on interactions that are not currently understood with either genetic variation elsewhere or the environment of the sample studied.

Adiponectin↗

Closing the gap between clinical research and clinical practice: can outcome studies with thiazolidinediones improve our understanding of type 2 diabetes?

Recent clinical research has provided a wealth of information to support optimal management strategies in type 2 diabetes mellitus (T2DM). In particular, outcome studies appropriately have had an increasingly important impact on clinical decision-making. Additional, new data are required, however, to close the current gaps in clinical knowledge and improve patient outcomes in T2DM. These outcome studies are particularly important in assessing the long-term benefit of newer agents for which data are available for short-term glycaemic control, effects on lipids and some data on non-traditional cardiovascular risk markers, but outcome data for harder end points relevant to the natural history of T2DM, particularly beta-cell function, are lacking. Outcome studies such as ADOPT and DREAM are investigating the impact of thiazolidinediones (TZDs) on beta-cell function and disease progression in T2DM and impaired glucose tolerance, respectively, the results of which are eagerly anticipated. The primary focus of this article is on TZD outcome studies evaluating beta-cell function and disease progression.

Diabetes Mellitus, Type 2↗

Prevalence of risk for type 2 diabetes in school children.

According to the Centers for Disease Control and Prevention, 1 in 3 children born in 2000 in the United States will become diabetic. The odds are higher for African American and Hispanic children as nearly 50% of them will develop diabetes. Random screening is not effective in identifying children at risk for type 2 diabetes mellitus (T2DM); therefore, there is a need to apply screening strategies that guide the development of appropriate primary prevention efforts. To assess the prevalence of risk factors for T2DM, 1066 fifth-grade children were screened using American Diabetes Association guidelines. Overall, 22.6% were found at risk; African American and Hispanic children were almost 8 times more likely to be at risk when compared to Caucasians (odds ratio = 7.41 and 7.87). Children who reported watching TV/playing video games 2 or more hours/day were 73% more likely to be at risk. Children identified to be at risk were referred to their primary care provider and were invited to participate in a counseling session. The environmental risk factors for T2DM identified in this study are modifiable and should be targeted in preventive interventions at the school and community level to reduce overweight and consequently prevent T2DM in children, especially among minority children.

Anthropometry↗

Acanthosis nigricans: relation with type 2 diabetes mellitus, anthropometric variables, and body mass in Indians.

OBJECTIVE: To determine the prevalence of acanthosis nigricans (AN) in type 2 diabetes mellitus (T2DM) and its correlation with various anthropometric measurements in Indians. METHODS: One hundred and fifty consecutive subjects with T2DM attending the diabetes clinic at a tertiary referral centre in North India were considered as cases and 150 age and sex matched healthy attendants of non-diabetic subjects as controls. All the cases and controls were screened for the presence of AN and its severity. Anthropometric measurements of all of them were measured in standard method. Regression analysis was done to determine the association of AN with T2DM and various anthropometric measurements. RESULTS: The prevalence of AN in subjects with diabetes and healthy controls was 62.6% and 40% respectively, and this difference was significant (p<0.05). Body mass index (BMI) between cases and controls was comparable by chance. There was a statistically significant correlation of increasing severity of AN with increasing BMI, waist circumference, hip circumference, waist-hip ratio, skinfold thickness, and body fat percentage in diabetic patients. However, in regression analysis after considering all the confounding factors there was a significant correlation of AN, only with diabetes mellitus and BMI. CONCLUSIONS: Indians have high prevalence of AN and it is an independent cutaneous marker of both T2DM and BMI.

Acanthosis Nigricans↗

Uncoupling protein-2 polymorphisms in type 2 diabetes, obesity, and insulin secretion.

The onset of type 2 diabetes (T2DM) is preceded by obesity, insulin resistance, and impaired beta-cell function. Uncoupling protein-2 (UCP2) is a widely expressed inner mitochondrial membrane protein. Common polymorphisms of the UCP2 gene have been implicated in diabetes, in obesity, and with changes in UCP2 mRNA levels. We tested the hypothesis that common UCP2 variants influence T2DM susceptibility in four parallel studies of separate populations. We typed the -866 promoter (G/A) variant, a nonsynonymous (Ala55Val or A55V) single-nucleotide polymorphism in exon 4, and a 45-nt insertion in the 3'-untranslated (3'UTR) region. Study populations included a case-control population study, a family-based association study, and a metabolic study of individuals who had been characterized for insulin sensitivity and secretion. To evaluate UCP2 mRNA levels, we examined a fourth population of subjects, who had undergone subcutaneous fat biopsy. All three variants showed a trend to an association with T2DM (P = 0.05 to 0.07) in the population but not the family-based association study. The 3' insertion/deletion (3'UTR I/D) variant was associated with body mass index (BMI, P = 0.035) among nondiabetic family members. Haplotype combinations were significantly associated with BMI (P = 0.028), triglyceride levels (P = 0.026), and fasting insulin (P = 0.029); highest values for the three traits were observed in individuals with the heterozygous combination GVI/AVD. In the metabolic study, all three variants were associated with an index of beta-cell compensation for insulin sensitivity (disposition index), particularly in interaction with family membership (P < 0.000001). Individuals homozygous for the -866 A allele had decreased adipose mRNA levels relative to GG homozygous individuals (P = 0.009), but the 3'UTR I/D variant had no impact on mRNA levels. We confirm modest effects of UCP2 variants on BMI and T2DM and show significant effects on insulin secretion in interaction with family-specific factors. However, the associated allele and the effects on gene expression are opposite to those reported previously.

Adipocytes↗