Iskandar Idris

Protein kinase C activation: isozyme-specific effects on metabolism and cardiovascular complications in diabetes

Abstract Protein kinase C (PKC) is a family of multifunctional isoenzymes, activated by diacylglycerols (DAGs), which play a central role in signal transduction and intracellular crosstalk by phosphorylating at serine/threonine residues an array of substrates, including cell-surface receptors, enzymes, contractile proteins, transcription factors and other kinases. Individual isozymes vary in their pattern of tissue and subcellular distribution, function and Ca2+/phospholipid cofactor requirements, and in diabetes there is widespread activation of the DAG-PKC pathway in metabolic, cardiovascular and renal tissues. In liver, muscle and adipose tissue, PKC isozymes have been implicated both as mediators and inhibitors of insulin action. Activation of DAG-sensitive PKC isoforms, such as PKC-θ and PKC-ɛ, down-regulates insulin receptor signalling and could be an important biochemical mechanism linking dysregulated lipid metabolism and insulin resistance in muscle. On the other hand, atypical PKC isozymes, such as PKC-ζ and PKC-λ, have been identified as downstream targets of PI-3-kinase involved in insulin-stimulated glucose uptake, especially in adipocytes. Glucose-induced de novo synthesis of (palmitate-rich) DAG and sustained isozyme-selective PKC activation (especially but not exclusively PKC-β) has been strongly implicated in the pathogenesis of diabetic microangiopathy and macroangiopathy through a host of undesirable effects on endothelial function, VSM contractility and growth, angiogenesis, gene transcription (in part by MAP-kinase activation) and vascular permeability. Interventions that increase DAG metabolism (e. g. vitamin E) and/or inhibit PKC isozymes (e. g. the β-selective inhibitor LY333 531) ameliorate the biochemical and functional consequences of DAG-PKC activation in experimental diabetes, for example improving retinal blood flow and albuminuria in parallel with reductions in membrane-associated PKC isozyme activities. Thus, a greater understanding of the functional diversity and pathophysiological regulation of PKC isozymes is likely to have important clinical and therapeutic benefits. [Diabetologia (2001) 44: 659–673]

Is diabetes a coronary risk equivalent? Systematic review and meta‐analysis

Aims  To determine whether patients with diabetes without prior myocardial infarction (MI) have the same risk of total coronary heart disease (CHD) events as non‐diabetic patients with previous myocardial infarction.

Obstructive sleep apnoea is independently associated with the metabolic syndrome but not insulin resistance state

Obstructive sleep apnoea (OSA) is a cardio-metabolic disorder. Whether metabolic syndrome (MS), insulin resistance (IR) and albuminuria are independently associated with OSA is unclear, but defining the interactions between OSA and various cardiovascular (CV) risk factors independent of obesity facilitates the development of therapeutic strategies to mitigate their increased CV risks. We prospectively recruited 38 subjects with OSA and 41 controls. Anthropometric measurements, glucose, lipids, insulin and blood pressure (BP) were measured after an overnight fast. IR state was defined as homeostasis model assessment (HOMA) value >3.99 and MS diagnosed according to the International Diabetes Federation (IDF) criteria. Subjects with OSA were more obese, more insulin resistant, more hyperglycaemic, had higher Epworth score (measure of day time somnolence) and systolic blood pressure levels. The prevalence of MS was higher in OSA compared with non-OSA subjects (74% vs 24%, p < 0.001). The prevalence of microalbuminuria in both groups was negligible. Logistic regression adjusted for age, BMI and smoking showed that the patient with OSA was 5.9 (95% CI 2.0–17.6) times more likely to have MS than non-OSA patient. Triglyceride (p = 0.031), glucose (0.023) and Epworth score (0.003) values were independently associated with OSA after adjusting for BMI and other covariates whilst IR status was found not to be significant. Using the ROC curve analysis, we found that a waist circumference of >103 cm would predict MS in patients with OSA at 75–78% sensitivity and 61–64% specificity. The agreement between MS and IR state in this cohort is poor. Thus, OSA is associated with MS independent of obesity predominantly due to increased triglyceride, glucose and Epworth score values but not IR or microalbuminuria status. This observation suggests an alternative pathogenic factor mediating the increased cardiovascular risk in patients with OSA and MS, other than that due to IR. The independent link between Epworth score and MS in patients with OSA implicates the role of daytime sleepiness and chronic hypoxia as a potential mediator. Given the discordant between MS and IR state, measurement of waist is useful for predicting mainly MS but not insulin resistance status in patients with OSA. Appropriate pharmacological intervention targeting these independent factors is important in reducing the increased CV risks among patients with OSA.

Sodium–glucose co‐transporter‐2 inhibitors: an emerging new class of oral antidiabetic drug

The sodium–glucose co‐transporter‐2 (SGLT2) is a low‐affinity transport system that is specifically expressed in the kidney and plays an important role in renal glucose reabsorption in the proximal tubule. Competitive inhibition of SGLT2 therefore represents an innovative therapeutic strategy for the treatment of hyperglycaemia and/or obesity in patients with type 1 or type 2 diabetes by enhancing glucose and energy loss through the urine. The observation that individuals with familial renal glycosuria maintain normal long‐term kidney function provides some reassurance that this mode of action will not adversely affect renal function. Intense research in this therapeutic area has led to the discovery of novel SGLT2 inhibitors, each with different chemical, pharmacodynamic and pharmacokinetic profiles. This review outlines the biology, expression and pleotropic activity of the SGLT system and the pharmacological profile of SGLT2 inhibitors and provides a summary of preclinical and limited clinical data available to characterize the efficacy, safety and potential clinical utility of SGLT2 inhibitors in the management of diabetes.

Exendin-4 increases insulin sensitivity via a PI-3-kinase-dependent mechanism: contrasting effects of GLP-1.

The insulinotropic agent, exendin-4, is a long-acting analogue of glucagon-like peptide-1 (GLP-1) which improves glucose tolerance in humans and animals with diabetes, but the underlying mechanisms and the effects of exendin-4 on peripheral (muscle/fat) insulin action are unclear. Previous in vivo and clinical studies have been difficult to interpret because of complex, simultaneous changes in insulin and glucagon levels and possible effects on hepatic metabolism. Thus, the comparative effects of exendin-4 and GLP-1 on insulin-stimulated 2-[3H]deoxyglucose (2-DOG) uptake were measured in fully differentiated L6 myotubes and 3T3-adipocytes, including co-incubation with inhibitors of the PI-3-kinase (wortmannin) and mitogen-activated protein (MAP) kinase (PD098059) pathways. In L6 myotubes, there was a concentration-dependent and PI-3-kinase-dependent increase in insulin-stimulated 2-DOG uptake with exendin-4 and GLP-1, e.g. for exendin-4 the C(I-200) value (concentration of insulin required to increase 2-DOG uptake 2-fold) decreased from 1.3 +/- 1.4 x 10(-7)M (insulin alone, n=16) to 5.9 +/- 1.3 x 10(-8)M (insulin+exendin-4 0.1nM, n=18, P<0.03). A similar insulin-sensitizing effect was observed with exendin-4 in 3T3-adipocytes, but GLP-1 had no effect on adipocyte insulin sensitivity. In conclusion, this is the first direct evidence showing that exendin-4 increases insulin-stimulated glucose uptake in muscle and fat derived cells via a pathway that involves PI-3-kinase activation. Furthermore, the contrasting responses of exendin and GLP-1 in 3T3-adipocytes suggest that the peripheral insulin-sensitizing effect of exendin-4 (in contrast to the insulinotropic effect) does not involve the GLP-1 receptor pathway.

The effect of anaemia and abnormalities of erythrocyte indices on HbA1c analysis: a systematic review.

Aims/hypothesisThe use of HbA1c for the diagnosis of diabetes is now widely advocated despite caveats to its use. Anaemia is cited as a major confounder to this use; however, the effect of erythrocyte indices and to what degree anaemia influences HbA1c levels is not known.MethodsA systematic electronic database search of MEDLINE, EMBASE, the Cumulative Index to Nursing & Allied Health Literature (CINAHL) and the Cochrane Library was conducted for relevant articles published between January 1990 and May 2014. Included studies had at least one measurement of HbA1c and glucose, and a least one index of haematinic deficiency, involving non-pregnant adults, not known to have diabetes.ResultsA total of 12 articles from 544 were included. The majority of studies focused on iron deficiency anaemia (IDA) and, in general, demonstrated that the presence of iron deficiency with or without anaemia led to an increase in HbA1c values compared with controls, with no concomitant rise in glucose indices. Data on the effects of other indices of erythrocyte abnormalities on HbA1c are limited but show a possible decrease in HbA1c values with non-iron deficiency forms of anaemia.Conclusions/interpretationHbA1c is likely to be affected by iron deficiency and IDA with a spurious increase in HbA1c values; conversely, non-IDA may lead to a decreased HbA1c value. This may lead to confusion when diagnosing diabetes using HbA1c. This review clearly identifies the need for more evidence, especially in identifying the types and degrees of anaemia likely to have significant impact on the reliability of HbA1c.

Early onset type 2 diabetes: risk factors, clinical impact and management.

Early onset type 2 diabetes mellitus (T2DM) is increasingly prevalent with a significant impact on the individual, healthcare service delivery and planning. The individuals are likely to be obese, lead a sedentary lifestyle, have a strong family history of T2DM, be of black and minority ethnic (BME) origin and come from a less affluent socioeconomic group. They have a heightened risk of developing microvascular and macrovascular complications, often at an earlier stage and with greater frequency than seen in type 1 diabetes. As such, early and aggressive risk factor management is warranted. Early onset T2DM is complex and impacts on service delivery with a need for multidisciplinary care of complications and comorbidities’, in addition to adequate educational and psychological support. This review on the impact of early onset T2DM provides the latest insights into this emerging epidemic.

Effects of Sleep Apnea Severity on Glycemic Control in Patients with Type 2 Diabetes Prior to Continuous Positive Airway Pressure Treatment

BACKGROUND Obstructive sleep apnea (OSA), a highly prevalent condition, is independently associated with increased risks of developing type 2 diabetes mellitus (T2D) and metabolic syndrome. It is unclear, however, if the severity of OSA has any impact on glycemic control among patients with T2D. We therefore aimed to determine the independent association between OSA severity and glycosylated hemoglobin (HbA1c) in patients with T2D. METHODS This was an observational cross-sectional study of 52 consecutive patients attending the diabetes obesity clinic between January 2008 to February 2010 with risk factors for sleep apnea and who underwent polysomnography study. Clinical, demographic, and lifestyle data were recorded using a questionnaire. RESULTS Prevalence of OSA in this clinical cohort was 58%. After adjusting for age, gender, body mass index, duration of diabetes, and insulin dose, increased severity of OSA was associated with increased HbA1c levels (P<0.014 for linear trend). A plateau effect between HbA1c and OSA severity was, however, noted from moderate to severe OSA levels. The adjusted mean values of HbA1c in each OSA category were 8.62% for none, 9.36% for mild, 10.61% for moderate, and 9.91% for severe. No significant associations were noted between liver transaminase level with OSA severity (P=0.324), between body mass index with OSA severity (P=0.278), or between HbA1c levels with the Epworth Score (a measure of daytime sleepiness) (P=0.46). CONCLUSIONS Increased severity of OSA is independently associated with worsening glycemic control following adjustment of various confounders, including insulin dosage. We would hypothesize therefore that identification and treating OSA among patients with T2D may confer benefits in improving glycemic control.

Association Between Thiazolidinedione Treatment and Risk of Macular Edema Among Patients With Type 2 Diabetes

BACKGROUND Findings of prior studies have been inconclusive about the ocular effects of thiazolidinediones on diabetic macular edema (DME). We evaluated, in patients with type 2 diabetes (T2D), the short-term and long-term risks of developing DME among users vs nonusers of thiazolidinediones. METHODS A retrospective cohort study of 103,368 patients with T2D and no DME at baseline using The Health Improvement Network (THIN) database. Clinical, biochemical, and demographic information was obtained for the period January 1, 2000, through November 30, 2009. RESULTS At 1 year, the incidence of DME was 1.3% (n = 41) and 0.2% (n = 227) among thiazolidinedione users (n = 3227) and nonusers (n = 100,141), respectively (odds ratio [OR], 5.7 [95% CI, 4.1-7.9]). After Cox multiple regression analysis (adjusted for age; systolic blood pressure; levels of lipids and hemoglobin A(1c); and use of aspirin, fibrates, insulin, oral antidiabetic drugs, or renin-angiotensin system blockers), multiple imputation analysis to adjust for missing values, and propensity score analysis to exclude for any selection bias, thiazolidinedione use was associated with an increased risk of DME at 1-year follow-up (OR, 2.3 [95% CI, 1.5-3.6]) and 10-year follow-up (hazard ratio [HR], 2.3; [95% CI, 1.7-3.0]). The effect was similar for pioglitazone and rosiglitazone. Combination therapy with insulin plus a thiazolidinedione was associated with a higher risk of DME after propensity score adjustment (HR, 3.0 [95% CI, 1.5-5.9]), while aspirin use (HR, 0.6 [95% CI, 0.4-0.9]) and angiotensin-converting enzyme inhibitor use (HR, 0.4 [95% CI, 0.2-0.7]) were associated with a reduced risk of DME. CONCLUSION Among patients with T2D, treatment with a thiazolidinedione was associated with an increased risk of DME at 1-year and 10-year follow-up evaluations.

Protein kinase C inhibition and diabetic retinopathy: a shot in the dark at translational research.

Translational research in practice: a PKCβ inhibitor for diabetic retinopathy