Bile acid changes after metabolic surgery are linked to improvement in insulin sensitivity.

BACKGROUND: Metabolic surgery is associated with a prompt improvement in insulin resistance, although the mechanism of action remains unknown. The literature on bile acid changes after metabolic surgery is conflicting, and insulin sensitivity is generally assessed by indirect methods. The aim of this study was to investigate the relationship between improvement in insulin sensitivity and concentration of circulating bile acids after biliopancreatic diversion (BPD) and Roux-en-Y gastric bypass (RYGB). METHODS: This was a prospective observational study of nine patients who underwent BPD and six who had RYGB. Inclusion criteria for participation were a BMI in excess of 40 kg/m2 , no previous diagnosis of type 2 diabetes and willingness to participate. Exclusion criteria were major endocrine diseases, malignancies and liver cirrhosis. Follow-up visits were carried out after a mean(s.d.) of 185·3(72·9) days. Fasting plasma bile acids were assessed by ultra-high-performance liquid chromatography coupled with a triple quadrupole mass spectrometer, and insulin sensitivity was measured by means of a hyperinsulinaemic-euglycaemic clamp. RESULTS: A significant increase in all bile acids, as well as an amelioration of insulin sensitivity, was observed after metabolic surgery. An increase in conjugated secondary bile acids was significantly associated with an increase in insulin sensitivity. Only the increase in glycodeoxycholic acid was significantly associated with an increase in insulin sensitivity in analysis of individual conjugated secondary bile acids. CONCLUSION: Glycodeoxycholic acid might drive the improved insulin sensitivity after metabolic surgery.

The DEXLIFE study methods: identifying novel candidate biomarkers that predict progression to type 2 diabetes in high risk individuals.

The incidence of type 2 diabetes (T2D) is rapidly increasing worldwide and T2D is likely to affect 592 million people in 2035 if the current rate of progression is continued. Today, patients are diagnosed with T2D based on elevated blood glucose, either directly or indirectly (HbA1c). However, the information on disease progression is limited. Therefore, there is a need to identify novel early markers of glucose intolerance that reflect the underlying biology and the overall physiological, metabolic and clinical characteristics of progression towards diabetes. In the DEXLIFE study, several clinical cohorts provide the basis for a series of clinical, physiological and mechanistic investigations in combination with a range of--omic technologies to construct a detailed metabolic profile of high-risk individuals across multiple cohorts. In addition, an exercise and dietary intervention study is conducted, that will assess the impact on both plasma biomarkers and specific functional tissue-based markers. The DEXLIFE study will provide novel diagnostic and predictive biomarkers which may not only effectively detect the progression towards diabetes in high risk individuals but also predict responsiveness to lifestyle interventions known to be effective in the prevention of diabetes.

Depressive symptoms, insulin sensitivity and insulin secretion in the RISC cohort study.

AIM: This study explored the association of depressive symptoms with indices of insulin sensitivity and insulin secretion in a cohort of non-diabetic men and women aged 30 to 64 years. METHODS: The study population was derived from the 3-year follow-up of the Relationship between Insulin Sensitivity and Cardiovascular Disease Risk (RISC) study. Presence of significant depressive symptoms was defined as a Center for Epidemiologic Studies Depression Scale (CES-D) score ≥ 16. Standard oral glucose tolerance tests were performed. Insulin sensitivity was assessed with the oral glucose insulin sensitivity (OGIS) index. Insulin secretion was estimated using three model-based parameters of insulin secretion (beta-cell glucose sensitivity, the potentiation factor ratio, and beta-cell rate sensitivity). RESULTS: A total of 162 out of 1027 participants (16%) had significant depressive symptoms. Having significant depressive symptoms was not related to either OGIS [standardized beta (ß) -0.033; P=0.24] or beta-cell glucose sensitivity (ß -0.007; P=0.82). Significant depressive symptoms were related to decreased beta-cell rate sensitivity (odds ratio for significant depressive symptoms of the lowest vs. highest quartile of beta-cell rate sensitivity was 2.04; P=0.01). Also, significant depressive symptoms were associated with a statistically significant decrease in the potentiation factor ratio in unadjusted models, but not in the fully adjusted model. CONCLUSION: Depressive symptoms were not related to insulin sensitivity and tended to be weakly associated to some parameters of insulin secretion in non-diabetic individuals. Prospective studies are needed to study the temporal association between depression and insulin secretion.

Gender-specific differences in carotid intima-media thickness and its progression over three years: a multicenter European study.

BACKGROUND AND AIMS: This multicentre European study evaluated, in a young-to-middle-aged healthy population without carotid atherosclerosis, the gender-related differences in carotid intima-media thickness (IMT) and its short-term (3-year) progression, and whether these differences are related to different vascular ageing rate, cardiovascular risk profile or different susceptibility to family predisposition to cardiovascular diseases (CVD). METHODS AND RESULTS: 366 men and 422 women (age between 30 and 60 years) underwent B-mode carotid ultrasound at baseline and after 3-year follow-up period. IMT in 3 carotid segments was higher in men than in women (p < 0.0001 for all segments). When evaluated according to age decade, differences between men and women disappeared in the 6th decade, as in this decade a 3-year IMT progression rate accelerated in women (p < 0.05 as compared to the 4th and 5th age decade). Age was a major determinant of baseline all-segment IMT in women; in men all-segment IMT was influenced by age and LDL-cholesterol. IMT progression did not correlate with established cardiovascular risk factors, their short-term changes or family predisposition to CVD. Yet, a 3-year IMT progression in common carotid artery (CCA) was higher in men (p = 0.01) and women (p < 0.01) in whom relative Framingham risk increased during the corresponding period. CONCLUSION: This study provides reference values on IMT and its short-term progression in healthy young-to-middle-aged population, and demonstrates gender-related differences in the susceptibility of carotid wall to ageing and LDL-cholesterol. Increase in Framingham risk accelerated a short-term CCA IMT progression rate in both genders, whereas family predisposition to CVD did not influence carotid IMT.

Estimating insulin sensitivity and beta cell function: perspectives from the modern pandemics of obesity and type 2 diabetes.

The 1985 manuscript describing the HOMA model, by Matthews and colleagues, is the most cited paper in the history of Diabetologia. In this edition of 'Then and now' we assess the impact of this seminal paper by considering the contribution of this elegant work in the context of the most rapidly changing period in the history of diabetes. HOMA was born in the middle of an 'era' of insulin resistance, and was subsequently nurtured and grew during the 'eras' of insulin sensitisers and diabetes prevention. From the modern era of insulin resistance onward, researchers have sought a convenient method for measuring insulin sensitivity and secretion, and found this in HOMA. However, the explosion in the prevalence of diabetes clearly underlines that an understanding of insulin resistance and how it can be measured has been insufficient to make any impact on the growing pandemic of diabetes. Knowledge of individual physiology is important, but the dramatic impact of the modern environment may be the factor that has escaped attention until very recently. An optimist can only state that the coming 'era' in diabetes research will be a period of true translation of scientific insight and implementation of effective disease prevention.

Globalization, immigration and diabetes self-management: an empirical study amongst immigrants with type 2 diabetes mellitus in Ireland.

BACKGROUND: We have previously reported that immigrants in Ireland have poorer glycemic control compared with a matched population of Irish patients. This may be associated with poor diabetes self-care and low health literacy. AIM: To compare the diabetes self-care profile of non-Irish-national patients i.e. immigrant patients (IM) and Irish patients (IR) attending a hospital diabetes clinic and to evaluate differences in health literacy between the two cohorts. METHODS: We studied the differences in diabetes self-management between 52 randomly selected non-Irish-national patients with type 2 diabetes and 48 randomly selected Irish/Caucasian patients. Rapid Estimate of Adult Literacy in Medicine (REALM) was used to assess health literacy. RESULTS: IM had poorer glycemic control than IR (HbA1c 8.0 +/- 1.9 vs. 6.9 +/- 1.4%, P < 0.005). A significant proportion of IM forget to monitor their daily blood glucose (42.1% vs. 12.5%, P < 0.05). Family support is more important amongst IM in performing daily blood glucose monitoring (75% vs. 47.7%, P < 0.05), taking medications (81.7% vs. 42.2%, P = 0.01) and following an appropriate meal plan (87.6% vs. 62.2%, P < 0.05). Fifty-three percent can only understand simple or familiar questions about their diabetes care; 65.9% can only provide information on simple or familiar topics about their diabetes. Health literacy was found to be lower in the IM groups when assessed using REALM (52.7 vs. 61.4, P = 0.01). CONCLUSION: Those providing diabetes education and care need to be aware of differing patient expectations regarding family involvement in the care of their diabetes and the possible contribution of language problems and lower health literacy to a limited understanding of diabetes self-care.

Correlation of the leptin:adiponectin ratio with measures of insulin resistance in non-diabetic individuals.

AIMS/HYPOTHESIS: Obesity is the dominant cause of insulin resistance. In adult humans it is characterised by a combination of adipocyte hypertrophy and, to a lesser extent, adipocyte hyperplasia. As hypertrophic adipocytes secrete more leptin and less adiponectin, the plasma leptin:adiponectin ratio (LAR) has been proposed as a potentially useful measure of insulin resistance and vascular risk. We sought to assess the usefulness of the LAR as a measure of insulin resistance in non-diabetic white adults. METHODS: Leptin and adiponectin levels were measured in 2,097 non-diabetic individuals from the Ely and European Group for the Study of Insulin Resistance (EGIR) Relationship between Insulin Sensitivity and Cardiovascular Risk (RISC) study cohorts. LAR was compared with fasting insulin and HOMA-derived insulin sensitivity (HOMA-S) in all individuals and with the insulin sensitivity index (M/I) from hyperinsulinaemic-euglycaemic clamp studies in 1,226 EGIR RISC participants. RESULTS: The LAR was highly correlated with HOMA-S in men (r = -0.58, p = 4.5 x 10(-33) and r = -0.65, p = 1.1 x 10(-66) within the Ely and EGIR RISC study cohorts, respectively) and in women (r = -0.51, p = 2.8 x 10(-36) and r = -0.61, p = 2.5 x 10(-73)). The LAR was also strongly correlated with the clamp M/I value (r = -0.52, p = 4.5 x 10(-38) and r = -0.47, p = 6.6 x 10(-40) in men and women, respectively), similar to correlations between HOMA-S and the M/I value. CONCLUSIONS/INTERPRETATION: The leptin:adiponectin ratio is a useful measure of insulin resistance in non-diabetic white adults. These data highlight the central role of adipocyte dysfunction in the pathogenesis of insulin resistance. Given that variations between fasting and postprandial leptin and adiponectin levels tend to be small, the leptin to adiponectin ratio might also have potential value in assessing insulin sensitivity in the non-fasted state.

The Leu262Val polymorphism of presenilin associated rhomboid like protein (PARL) is associated with earlier onset of type 2 diabetes and increased urinary microalbumin creatinine ratio in an Irish case-control population.

AIMS: Environmental and genetic factors contribute to the evolution of type 2 diabetes (T2DM). Presenilin associated rhomboid like protein (PARL) is a mitochondrial protein that has been implicated in T2DM in both the rodent Psammomys obesus and in humans. The SNP variant (Leu262Val) in PARL has been shown to be associated with hyperinsulinaemia in an age-dependent manner in a US non-diabetic, cohort. However, this finding has not been replicated in UK cohorts. We studied Leu262Val associations in an Irish Caucasian T2DM case-control population. METHODS: An RFLP-PCR assay using BstN I was used to assess Leu262Val genotype in a total of 613 subjects, 421 with T2DM and 192 controls. RESULTS: In the control group genotype frequencies were as follows 27.37% (GG), 51.58% (CG) and 21.05% (CC), while in the group with T2DM 30.64% (GG), 47.74% (CG) and 21.62% (CC). We observed no association between Leu262Val variant and T2DM nor was there an association with plasma insulin concentrations or BMI. There was no interaction between age and fasting plasma insulin concentration. However, in the group with T2DM the C allele was associated with higher urinary albumin to creatinine ratio while the GG genotype was associated with an earlier age of onset of T2DM. CONCLUSION: The Leu262Val polymorphism of PARL is not associated with markers of insulin resistance. However, in subjects with T2DM, genetic variation at this locus may indicate earlier onset of T2DM and increased susceptibility to nephropathy and cardiovascular complications.

Elevated blood pressure in overweight and obese Irish children.

BACKGROUND: The Irish childhood obesity epidemic, one of the highest ranking internationally, represents a major threat to public health. We sought to perform a retrospective observational study of a clinic based cohort of obese Irish children. METHODS: Clinical data relating to gender, age, height, weight, body mass index and blood pressure were analysed, from 206 children referred to a paediatric endocrine referral centre over a 15-year period for assessment of obesity. RESULTS: Younger patients tended to have a higher standardised body mass index at initial presentation; 92% of boys and 96% of girls referred were obese (age-related BMI >/= 95th percentile). Boys (51%) and girls (49%) had initial blood pressure measurements in the hypertensive range. There was a correlation between the degree of obesity and systolic blood pressure, particularly in boys. CONCLUSIONS: Obese Irish children present with significant long-term health risks, including hypertension at baseline.

Immigrant patients with type 2 diabetes mellitus have poorer initial and on-going glycemic control than a matched population of Irish patients.

We compared the glycemic and cardiovascular risk status of non-Caucasian patients with type 2 diabetes mellitus (T2DM) who recently emigrated to Ireland with a matched population of Irish patients. We identified 105 non-Caucasian patients with T2DM who recently emigrated to Ireland and compared them with 105 Irish patients with T2DM, who were matched for age, sex and duration of diabetes. Immigrants with T2DM had significantly worse initial (9.8% vs 9.1%, p<0.05) and on-going (8.3% vs 7.1, p<0.05) glycemic control and higher microalbumin to creatinine ratio compared to the Irish patients. A greater proportion of immigrants with T2DM were on insulin therapy for their diabetes. Irish patients had significantly higher fasting triglyceride concentrations compared to the immigrants (1.9+/-0.1 mmol/l vs 1.6+/-0.1 mmol/l, p<0.05). This vulnerable population of immigrants with T2DM is currently at higher risk of complications of diabetes and warrants greater attention to glycemic control and control of other risk factors.

Adverse metabolic profiles in a cohort of obese Irish children.

BACKGROUND: The metabolic characteristics of obese Irish children are not well defined. We prospectively examined the relationship between the degree of obesity and glucose metabolism, insulin sensitivity and suspected non-alcoholic steatohepatosis (NASH) in a pilot study of obese Irish children. METHODS: We measured height, weight, body mass index (BMI), blood pressure, waist and hip circumference in 18 participants (mean age 15.5 years). Fasting blood glucose, insulin, lipid profile and alanine aminotransferase (ALT) concentrations were also measured. A standard 75 g oral glucose tolerance test was performed and insulin sensitivity was derived from this using a mathematical model--oral glucose insulin sensitivity. RESULTS: There were significant associations between the degree of obesity, insulin sensitivity and markers of liver steatosis. For example, when adjusted for pubertal status, there were significant associations between standardized BMI and insulin sensitivity (regression coefficient, beta = -70.1, P = 0.018) and ALT (beta = 20.7, P = 0.007). CONCLUSION: This study suggests that the degree of obesity is associated with lower insulin sensitivity and possible NASH in obese Irish children.

Early-onset type 2 diabetes in obese white subjects is characterised by a marked defect in beta cell insulin secretion, severe insulin resistance and a lack of response to aerobic exercise training.

AIMS/HYPOTHESIS: Early-onset type 2 diabetes is associated with marked visceral obesity and extreme insulin resistance, but its pathogenesis and response to treatment are not completely understood. We studied physical fitness, whole-body and hepatic glucose turnover, and insulin secretion in young obese Irish subjects before and after 3 months of aerobic exercise training. We hypothesised that exercise alone, with stable diet, should improve insulin sensitivity. MATERIALS AND METHODS: Anthropometric parameters and maximum volume of oxygen utilisation (VO(2max)) were measured in 13 subjects with type 2 diabetes and 18 non-diabetic control subjects, matched for age and BMI. Insulin sensitivity and hepatic glucose turnover were measured using the hyperinsulinaemic-euglycaemic clamp. Insulin secretion was assessed from an OGTT and a modified intravenous glucose tolerance test. Some subjects (seven type 2 diabetic, 14 non-diabetic control subjects) then completed a 12-week supervised aerobic exercise programme. All measurements were repeated on completion of the exercise programme. RESULTS: Type 2 diabetic subjects had higher WHR, systolic blood pressure and triacylglycerols than non-diabetic control subjects. They were significantly more insulin-resistant as measured both by the clamp and oral glucose insulin sensitivity. They also displayed marked defects in insulin secretion in response to oral and intravenous glucose challenges. Exercise intervention had no significant effect on whole-body or hepatic insulin sensitivity or insulin secretion. VO(2max) increased significantly in the non-diabetic control subjects, but not in the type 2 diabetic subjects after exercise training. CONCLUSIONS/INTERPRETATION: Young obese subjects with type 2 diabetes are severely insulin-resistant with marked loss of beta cell function compared with control subjects matched for age and obesity. Neither group responded metabolically to aerobic exercise intervention.

Exercise training increases insulin-stimulated glucose disposal and GLUT4 (SLC2A4) protein content in patients with type 2 diabetes.

AIMS/HYPOTHESIS: Exercise enhances insulin-stimulated glucose transport in skeletal muscle through changes in signal transduction and gene expression. The aim of this study was to assess the impact of acute and short-term exercise training on whole-body insulin-mediated glucose disposal and signal transduction along the canonical insulin signalling cascade. METHODS: A euglycaemic-hyperinsulinaemic clamp, with vastus lateralis skeletal muscle biopsies, was performed at baseline and 16 h after an acute bout of exercise and short-term exercise training (7 days) in obese non-diabetic (n=7) and obese type 2 diabetic (n=8) subjects. RESULTS: Insulin-mediated glucose disposal was unchanged following acute exercise in both groups. Short-term exercise training increased insulin-mediated glucose disposal in obese type 2 diabetic (p<0.05), but not in obese non-diabetic subjects. Insulin activation of (1) IRS1, (2) IRS2, (3) phosphotyrosine-associated phosphatidylinositol-3 kinase activity and (4) the substrate of phosphorylated Akt, AS160, a functional Rab GTPase activating protein important for GLUT4 (now known as solute carrier family 2 [facilitated glucose transporter], member 4 [SLC2A4]) translocation, was unchanged after acute or chronic exercise in either group. GLUT4 protein content was increased in obese type 2 diabetic subjects (p<0.05), but not in obese non-diabetic subjects following chronic exercise. CONCLUSIONS/INTERPRETATION: Exercise training increased whole-body insulin-mediated glucose disposal in obese type 2 diabetic patients. These changes were independent of functional alterations in the insulin-signalling cascade and related to increased GLUT4 protein content.

Downregulation of protein kinase B/Akt-1 mediates INS-1 insulinoma cell apoptosis induced by dominant-negative suppression of hepatocyte nuclear factor-1alpha function.

AIMS/HYPOTHESIS: Inactivating mutations in Tcf1, which encodes the transcription factor hepatocyte nuclear factor (HNF)-1alpha, cause maturity-onset diabetes of the young-3. We have previously shown that a dominant-negative mutant (DN-HNF-1alpha) renders INS-1 insulinoma cells sensitive to the mitochondrial apoptosis pathway, but the underlying alterations in signal transduction remain unknown. MATERIALS AND METHODS: Using a reverse tetracycline-dependent transactivator system, DN-HNF-1alpha-induced apoptosis was assessed by immunoblotting and caspase assays. Alterations in AKT1 kinase/protein kinase B (AKT1) survival signalling during DN-HNF-1alpha-induced apoptosis were investigated by phospho-specific immunodetection and transient transfection experiments. RESULTS: Induction of DN-HNF-1alpha caused significant changes in the activation-specific phosphorylation status of AKT1 that were preceded by a downregulation of Ins1 gene transcription. Phosphorylation of AKT1 at Ser473 was dramatically reduced after 36 to 48 h of DN-HNF-1alpha induction and coincided with maximal apoptosis activation. Overexpression of a constitutively active mutant of Akt1 rescued INS-1 cells from DN-HNF-1alpha-induced apoptosis, while ectopic expression of a dominant-negative mutant mimicked the effect of DN-HNF-1alpha on apoptosis activation. Pharmacological suppression of growth factor survival signalling through administration of the phosphatidylinositol-3 kinase (PI-3K) inhibitor wortmannin accelerated the induction of apoptosis by DN-HNF-1alpha. CONCLUSIONS/INTERPRETATION: These data suggest that a decrease in PI-3K/AKT1 survival signalling mediates DN-HNF-1alpha-induced apoptosis in insulin-secreting cells.

The cost of treating type 2 diabetes (CODEIRE).

Diabetes mellitus is the most common chronic metabolic disease and a major source of morbidity and mortality. Type 2 diabetes (T2D) is by far the most prevalent form of diabetes accounting for around 90% of cases worldwide. In recent years it has become apparent that a diabetes epidemic is unfolding as a result of increasing obesity, sedentary lifestyles and an ageing population. The enormity of the diabetes epidemic raises concern about the total cost to healthcare systems. This study was undertaken to investigate the direct healthcare costs of managing T2D in Ireland. Data was captured on 701 diabetes patients attending four diabetes centres. A bottom-up, prevalence-based design was used, which collected data on hospital resource use and clinical outcome measures over a 12-month period (1999/2000). The study was observational in nature, focusing on usual care of patients with T2D. Although the true prevalence of T2D in Ireland is unknown, conservative estimates are 3.9% for diagnosed diabetes and 6% for both diagnosed and undiagnosed diabetes. Using these figures the annual total direct cost was estimated at 377.2 million euro for diagnosed diabetes and 580.2 million euro for both diagnosed and undiagnosed diabetes. This corresponds to 4.1% and 6.4% of total healthcare expenditure respectively. Hospitalisations were the main driver of costs, accounting for almost half of overall costs, while ambulatory and drug costs accounted for 27% and 25% respectively. Hospitalisation costs were high because 60% of patients had developed complications. The most common microvascular and macrovascular complications were neuropathy and angina respectively. The annual cost of care for patients with microvascular and macrovascular complications were 1.8 and 2.9 times the cost of treating those without clinical evidence of complications respectively. The figure for patients with both types of complications was 3.8. This study shows that T2D is a very costly disease, largely due to the cost of and the management of complications. Many diabetes related complications are preventable, therefore it would appear a cost-effective approach for government to invest in the prevention of T2D and diabetes related complications.

Neurocysticercosis: a rare cause of seizure.

Neurocysticercosis is endemic in certain parts of the world, is rare in Europe and has never previously been described in the Irish healthcare setting. We report the case of a healthy male, originally from Guatemala, who presented to our hospital with a generalized tonic-clonic seizure presumed secondary to neurocysticercosis.

The cost of managing diabetic foot ulceration in an Irish hospital.

BACKGROUND: Little is known about the economic impact of diabetic foot ulceration in the Irish healthcare setting. AIM: Audit of diabetic foot ulcer admissions in St James's Hospital between April 2001 and March 2002. METHODS: Hospital charts were reviewed and costs were calculated on the length of patients' hospital stay and the cost of individual investigations performed. RESULTS: Thirty patients were admitted with diabetic foot ulceration as the primary complaint. Amputation was performed in eight patients, two patients with a non-healing ulcer died. The average duration of each hospital admission was 20.3+/-30.7 days. Net in-hospital expenditure was 704,689, an average of 23,489.63 per hospital admission. CONCLUSIONS: The management of diabetic foot ulceration has a significant economic impact on the Irish healthcare budget. Treatment should therefore be focused on primary prevention through specialised foot clinics and a multidisciplinary team approach to reduce this economic burden.