Postprandial insulin secretion pattern is associated with histological severity in non-alcoholic fatty liver disease patients without prior known diabetes mellitus

Background and Aim: Insulin resistance and diabetes mellitus (DM) are known to contribute to the progression of non‐alcoholic fatty liver disease (NAFLD). However, the relationship between glucose metabolism and NAFLD is not well known. In this study, we investigated whether secretion patterns of glucose and insulin could influence the histological severity in NAFLD patients without prior known type 2 DM. Methods: A 75‐g glucose tolerance test was performed on 173 biopsy‐proven NAFLD patients without prior known type 2 DM. Plasma glucose and insulin levels were analyzed periodically for 3 h after oral glucose loading. Results: Of the 173 NAFLD patients, 168 had non‐alcoholic steatohepatitis, whereas no patient had cirrhosis. Irrespective of the hemoglobin A1c levels, impaired glucose tolerance, including DM, was detected in 60% of the NAFLD patients. While the secretion pattern of glucose after glucose loading was similar among the NAFLD patients, postprandial insulin levels increased and delayed insulin secretion increased in severity in parallel with the aggravation of histological findings (fibrosis stages). Factors associated with advanced fibrosis were higher insulin levels at 120 min after oral glucose loading (P = 0.0001; odds ratio [OR], 3.56; 95% confidence interval [CI], 1.61–7.86), aspartate aminotransferase (P = 0.003; OR, 2.70; 95% CI: 1.19–6.12), and age (P = 0.02; OR, 2.49; 95% CI: 1.15–5.37) as determined by multivariate analysis. Conclusions: Postprandial hyperinsulinemia (but not glucose levels) was associated with advanced fibrosis. The oral glucose tolerance test should be considered in NAFLD patients without prior known type 2 DM in order to facilitate early therapeutic intervention.     

Post‐prandial insulin lispro vs. human regular insulin in prepubertal children with Type 1 diabetes mellitus

Aims To study whether post‐prandial insulin lispro (PL) could be used as a part of insulin therapy instead of premeal human regular insulin (HR) in prepubertal children with Type 1 diabetes mellitus (Type 1 DM). Patients and methods In this open, randomized cross‐over study patients used either PL or HR at breakfast and at dinner. After a 1‐month screening period, patients were randomized to treatment with PL or HR for 3 months and then they crossed over to the other insulin for an additional 3 months. The patients were 24 prepubertal children with Type 1 DM (median age 6.2 years, duration of diabetes 37 months). Home monitoring of 1‐day glucose profiles at meals (premeal, 1 h and 2 h after breakfast and after dinner) and HbA_1c were measured before randomization, before cross‐over, and at the last visit. Data on hypoglycaemic episodes were collected at each of the seven visits. The variables were compared between the two treatments. Results Of the patients 22/24 completed the study. There were no major differences in the glucose excursions between PL and HR after breakfast (mean ± sd : 1‐h PL 3.7 ± 4.7 vs. HR 2.9 ± 3.9 mmol/l, P = 0.3; 2‐h ?0.9 ± 5.4 vs. 0.3 ± 4.5 mmol/l, P = 0.2, respectively) or after dinner (1‐h PL ?2.5 ± 4.8 vs. HR ?0.4 ± 3.7 mmol/l, P = 0.07, 2‐h ?4.1 ± 5.2 vs. ?0.7 ± 5.0 mmol/l, P = 0.05, respectively). Mean change of HbA_1c was similar in both treatment groups (PL 0.2 ± 0.8% vs. HR ?0.4 ± 0.7%, P = 0.1). The frequency of hypoglycaemic episodes was 4.9 per patient per month during treatment with PL, and 4.4 during HR (P = 0.3). Conclusion Treatment with post‐prandial lispro as a meal insulin is as effective and safe as traditional treatment with regular insulin in young children. Diabet. Med. 18, 654–658 (2001)     

Impact of non‐alcoholic fatty liver disease on microalbuminuria in patients with prediabetes and diabetes

Background: It is unknown whether microalbuminuria is associated with non‐alcoholic fatty liver disease (NAFLD) among patients with prediabetes and type 2 diabetes mellitus (DM). This study investigated the association of NAFLD with microalbuminuria among patients with prediabetes and diabetes. Methods: We evaluated 1361 subjects who had an abnormal oral glucose tolerance test (OGTT) on routine screening. All participants were divided into two groups, prediabetes and newly diagnosed type 2 DM, and the association of NAFLD with metabolic parameters on microalbuminuria was analysed. Results: The patients with NAFLD had higher prevalence rates of microalbuminuria (6.3% vs 19%; P= 0.001 in prediabetes, 4.5% vs 32.6%; P < 0.001 in diabetes) and also had a greater albumin‐to‐creatinine ratio (14.6 ± 52.0 µg/mg Cr vs 27.7 ± 63.9 µg/mg Cr; P= 0.051 in prediabetes, 11.4 ± 21.4 µg/mg Cr vs 44.7 ± 76.4 µg/mg Cr; P < 0.001 in diabetes) than those without NAFLD. The logistic regression analysis showed that NAFLD was associated with increased rates of microalbuminuria (odds ratio 3.66; 95% confidence interval (CI) 1.31–10.20, P= 0.013 in prediabetes, odds ratio 5.47; 95% CI 1.01–29.61, P= 0.048 in diabetes), independently of age, sex, body mass index, waist circumference, liver enzymes, lipid profiles, HbA1c, insulin resistance as estimated by homeostasis model assessment, hypertension, smoking status and the metabolic syndrome. Conclusions: The results of our study revealed a strong relationship between microalbuminuria and NAFLD in the patients with prediabetes and newly diagnosed diabetes. Further studies are required to confirm whether NAFLD is a predictor of the development of microalbuminuria in patients with prediabetes and diabetes.     

Short‐Term Effect of Atorvastatin on Endothelial Function in Healthy Offspring of Parents with Type 2 Diabetes Mellitus

Endothelial function is impaired in healthy subjects at risk of type 2 diabetes mellitus (DM). We investigated whether endothelial dysfunction can be normalized by statin therapy in this potentially predisposed population. Flow‐mediated dilation (FMD) was measured in 56 first‐degree relatives (FDRs) (normotensive, normal glucose tolerance) and 20 age‐, sex‐, and BMI‐matched controls with no family history of DM. Other measurements included insulin resistance index using the homeostasis model of insulin resistance (HOMA_IR), plasma lipids, and markers of inflammation. The FDRs were then randomized and treated with atorvastatin (80 mg) or placebo daily in a 4‐week double‐blind, placebo‐controlled trial. The FDRs had significantly impaired FMD (4.4 ± 8.1% vs. 13.0 ± 4.2%; P < 0.001), higher HOMA_IR (1.72 ± 1.45 vs. 1.25 ± 0.43; P= 0.002), and elevated levels of plasma markers of inflammation—highly sensitive C‐reactive protein (hsCRP) (2.6 ± 3.8 mg/L vs. 0.7 ± 1.0 mg/L; P= 0.06), interleukin (IL)‐6 (0.07 ± 0.13 ng/mL vs. 0.03 ± 0.01 ng/mL; P < 0.001), and soluble intercellular adhesion molecule (sICAM) (267.7 ± 30.7 ng/mL vs. 238.2 ± 20.4 ng/mL; P < 0.001). FMD improved in the atorvastatin‐treated subjects when compared with the placebo‐treated subjects (atorvastatin, from 3.7 ± 8.5% to 9.8 ± 7.3%; placebo, from 3.9 ± 5.6% to 4.7 ± 4.2%; P= 0.001). There were also reductions in the levels of IL‐6 (0.08 ± 0.02 ng/mL vs. 0.04 ± 0.01 ng/mL; P < 0.001) and hsCRP (3.0 ± 3.9 mg/L vs. 1.0 ± 1.3 mg/L; P= 0.006). Our study suggests that treatment with atorvastatin may improve endothelial function and decrease levels of inflammatory markers in FDRs of type 2 DM patients.     

Twenty-four-hour profiles of plasma glucose, insulin, C-peptide and free fatty acid in subjects with varying degrees of glucose tolerance following short-term, medium-dose prednisone (20 mg/day) treatment: evidence for differing effects on insulin secretion and action

Objective To determine the time course and prandial effects of short‐term, medium‐dose prednisone on 24‐h metabolic patterns under standardized conditions. Context Glucocorticoids (GCs) adversely affect glucose homoeostasis but 24‐h profiles of glucose, insulin, C‐peptide and free fatty acids (FFAs) following short‐term, medium‐dose prednisone treatment in persons with varying degrees of glucose tolerance are not well defined. Design An open‐label cross‐sectional interventional study. Subjects Three groups were prospectively studied: persons with type 2 diabetes (T2DM; n = 7), persons ‘at risk’ for T2DM (AR; n = 8) and persons with normal glucose tolerance (NGT; n = 5). Methods Before and after 3‐day treatment with prednisone 20 mg each morning, subjects underwent 24‐h frequent blood sampling. Eucaloric mixed meals were provided at 08:00, 12:00 and 18:00 h. Insulin/glucose ratio provided an estimate of β‐cell response to meal stimuli. Measurements Plasma glucose, insulin, C‐peptide, haemoglobin A1c and FFA. Results Prednisone induced greater increases in glucose levels from midday (P = 0·001) to midnight (P = 0·02) in the T2DM than the AR and NGT groups. In contrast, insulin (P = 0·03) and C‐peptide (P = 0·04) levels decreased postbreakfast in the T2DM group, whereas no changes in the morning but higher C‐peptide levels (P = 0·03) from midday to midnight were observed in the AR group. In the T2DM group, insulin/glucose ratio decreased postbreakfast (P = 0·04) and increased postdinner (P = 0·03). Fasting glucose, insulin and C‐peptide levels were unchanged in all groups, and FFA levels modestly increased postdinner (P = 0·03) in the NGT group. Conclusion Short‐term, medium‐dose prednisone treatment induces postprandial hyperglycaemia in T2DM and AR predominantly from midday to midnight because of suppression of insulin secretion followed by decreased insulin action that dissipates overnight. Effective treatment of prednisone‐induced hyperglycaemia should target both rapid onset relative insulin deficiency and a less than 24‐h total duration of effect.     

Comparing hormonal and symptomatic responses to experimental hypoglycaemia in insulin‐ and sulphonylurea‐treated Type 2 diabetes

Aims Patients with diabetes rely on symptoms to identify hypoglycaemia. Previous data suggest patients with Type 2 diabetes develop greater symptomatic and hormonal responses to hypoglycaemia at higher glucose concentrations than non‐diabetic controls and these responses are lowered by insulin treatment. It is unclear if this is as a result of insulin therapy itself or improved glucose control. We compared physiological responses to hypoglycaemia in patients with Type 2 diabetes patients treated with sulphonylureas (SUs) or insulin (INS) with non‐diabetic controls (CON). Methods Stepped hyperinsulinaemic hypoglycaemic clamps were performed on 20 subjects with Type 2 diabetes, 10 SU‐treated and 10 treated with twice‐daily premixed insulin, and 10 age‐ and weight‐matched non‐diabetic controls. Diabetic subjects were matched for diabetes duration, glycated haemoglobin (HbA_1c) and hypoglycaemia experience. We measured symptoms, counterregulatory hormones and cognitive function at glucose plateaux of 5, 4, 3.5, 3 and 2.5 mmol/l. Results Symptomatic responses to hypoglycaemia occurred at higher blood glucose concentrations in SU‐treated than INS‐treated patients [3.5 (0.4) vs. 2.6 (0.5) mmol/l SU vs. INS; P = 0.001] or controls [SU vs. CON 3.5 (0.4) vs. 3.0 (0.6) mmol/l; P = 0.05]. They also had a greater increase in symptom scores at hypoglycaemia [13.6 (11.3) vs. 3.6 (6.1) vs. 5.1 (4.3) SU vs. INS vs. CON; P = 0.017]. There were no significant differences in counterregulatory hormone responses or impairment of cognitive function among groups. Conclusions Sulphonylurea‐treated subjects are more symptomatic of hypoglycaemia at a higher glucose level than insulin‐treated subjects. This may protect them from severe hypoglycaemia but hinder attainment of glycaemic goals.     

Adiponectin is an indicator of insulin resistance in non-obese prepubertal children born large for gestational age (LGA) and is affected by birth weight

Background and objective Being born as large for gestational age (LGA) has an increased risk of developing insulin resistance. Hypoadiponectinaemia is associated with insulin resistance. The aim of this study was to evaluate adiponectin levels and insulin resistance in association with body composition in LGA born non‐obese children at prepubertal ages. Patients and methods Thirty‐five (17 female and 18 male) LGA born non‐obese children (mean age 4·8 ± 0·3 years) were evaluated with respect to glucose, insulin, IGFBP‐1, leptin, adiponectin levels and body composition by DEXA. Their data were compared to that of non‐obese 49 (20 female, 29 male) appropriate for gestational age (AGA) children (mean age 3·8 ± 0·1 year). Results LGA children, who had similar body mass index standard deviation scores (BMI SDS) as AGA children, had significantly higher insulin (P = 0·043) and statistically borderline significant homeostasis model assessment‐insulin resistance (HOMA‐IR) levels (P = 0·054) than those of AGA children. Adiponectin levels were significantly lower in LGA than AGA children (P = 0·004) even after controlling for age, sex and BMI (P = 0·016). IGFBP‐1, leptin levels and body composition did not show a difference. When the LGA group was divided into subgroups according to birth weight, the analysis revealed that after controlling for BMI, being an LGA and having a higher birth weight in the upper half were associated with lower adiponectin levels (estimated marginal means of logarithmic adiponectin levels 2·6 ± 0·2 vs. 2·1 ± 0·2 µg/ml, P = 0·042). Conclusion LGA children have higher insulin and lower adiponectin levels than AGA children in spite of similar BMI. Adiponectin is a better indicator of insulin resistance in LGA children at prepubertal ages and is affected by birth weight.     

Elevated fasting plasma C‐peptide occurs in non‐diabetic individuals with fatty liver,irrespective of insulin resistance

Aims Studies have pointed to insulin resistance as a pathogenic factor in fatty liver. Although pancreatic B‐cell function is believed to be involved, its role is unclear. This study was undertaken to test whether fasting C‐peptide, an index of fasting B‐cell function, was related to intra‐hepatic fat (IHF) content in non‐diabetic humans. Methods We assessed, retrospectively, fasting plasma C‐peptide concentration in 31 patients with fatty liver and 62 individuals without fatty liver. The IHF content was measured by proton magnetic resonance spectroscopy (¹H‐MRS), while insulin sensitivity was estimated based on fasting plasma glucose and insulin with the homestasis model assessment (HOMA) 2 method. Results Age, sex and body mass index (BMI) were not different between groups. Patients with fatty liver had higher fasting insulin (P < 0.01), C‐peptide (P < 0.005) and lower insulin sensitivity (HOMA2‐%S). Fasting insulin alone explained 14% of the IHF content variability (P < 0.001); inclusion of fasting C‐peptide in multivariate regression explained up to 32% (P < 0.001). A subgroup analysis was performed by matching 1 : 1 for HOMA2‐%S. These data were analysed by conditional logistic regression which showed that, when HOMA2‐%S was matched between groups, fasting C‐peptide remained the only significant predictor of fatty liver. Conclusions Non‐diabetic individuals with fatty liver are characterized by increased fasting plasma C‐peptide concentration, irrespective of their insulin resistant state.     

Effect of insulin glargine on glycaemic control and weight in obese and non‐obese people with type 2 diabetes: data from the AT.LANTUS trial

Aims: To explore glucose lowering response to insulin initiation or switch to insulin glargine in obese and non‐obese individuals with type 2 diabetes mellitus (T2DM) and to examine weight gain and hypoglycaemic episodes in this group. Methods: Post hoc subgroup analysis using data of obese and non‐obese participants from a large multi‐centre (4555 participants with T2DM), multi‐national 24‐week randomized controlled trial of investigator titrated insulin glargine versus patient self‐managed titrated insulin glargine. This analysis was carried out to compare two subgroups: obese (≥30 kg/m²) and non‐obese (<30 kg/m²) participants. Results: The mean body mass index (BMI) values were 33.7 kg/m²(n = 1833) and 25.9 kg/m²(n = 2755) in obese and non‐obese subjects, respectively. There was a significant reduction in glycated haemoglobin (HbA1c) from baseline in both subgroups but no significant difference between subgroups (1.15 vs. 1.15%, p = 0.50). Overall, there was a 1.21 kg (s.d. 3.3) increase in weight in individuals who were non‐obese and a 1.08 kg (s.d. 3.9) increase in obese individuals (p = 0.67). There was no significant difference in the proportion of participants achieving an HbA1c of <7.0% at 6 months in both the subgroups (28.8 vs. 27.1%, p = 0.20). In multiple logistic regression, BMI was not a prognostic factor in achieving a target of HbA1c ≤ 7.0%. There was no significant difference in severe hypoglycaemic episodes between obese and non‐obese subgroups (1.3 vs. 1.0%); however, significantly more non‐obese individuals experienced nocturnal hypoglycaemic episodes(4.5 vs. 2.4%, p < 0.05). Conclusions: In this study, treatment with insulin glargine in people with T2DM was associated with a significant reduction in HbA1c without differential increase in weight gain in obese and non‐obese subgroups. Rates of severe hypoglycaemia were not different between obese and non‐obese subgroups.     

Erythrocytosis in offspring of mothers with Type 1 diabetes—are factors other than insulin critical determinants?

Aim Maternal diabetes is associated with polycythaemia and thrombocytopaenia in the offspring; however, the relationship with fetal hormones is unknown. We assessed the association of maternal glycaemic control, birthweight and fetal hormones with haematological indices in pregnancies complicated by maternal diabetes. Methods Prospective study using cord blood samples from 89 offspring of mothers with Type 1 diabetes (OT1DM) and 34 control offspring. Full blood count, insulin, leptin, adiponectin, cortisol, insulin‐like growth factor 1 (IGF‐1), insulin‐like growth factor binding protein 3, intercellular adhesion molecule 1 and C‐reactive protein were measured in the umbilical vein at birth. Results Haematocrit was higher in OT1DM (OT1DM 0.55 ± 0.17%, control offspring 0.51 ± 0.06%; P = 0.02). The difference in platelets count was not statistically significant [OT1DM 214 × 10⁹/l (173–259); control offspring 253 × 10⁹/l (180–310), P = 0.06]. Maternal glycated haemoglobin (HbA_1c) showed a moderate positive correlation with fetal haematocrit (r = 0.30, P = 0.02). Cord platelet counts were negatively associated with birthweight in OT1DM (r = ?0.27, P = 0.01). In multivariate models, cord insulin was not associated with haematocrit, but cord leptin was negatively associated with platelets in control offspring (P < 0.001) and OT1DM (P = 0.046), with additional contributions from male sex (P = 0.08) in OT1DM, and IGF‐1 (P = 0.04) and insulin (P = 0.04) in control offspring. Conclusions Fetal haematocrit is increased in response to diabetes in pregnancy and is related to maternal glycaemic control. Fetal hyperinsulinism, hyperleptinaemia or macrosomia, although readily demonstrable in this cohort, do not emerge as determinants of raised fetal haematocrit in OT1DM. Both increased birthweight and fetal leptin are negatively associated with platelet count.     

Strong association between insulin resistance in liver and skeletal muscle in non‐diabetic subjects

Objective To examine the association between insulin resistance in skeletal muscle and liver in non‐diabetic subjects. Research design and methods A total of 182 Mexican American subjects without Type 2 diabetes underwent an oral glucose tolerance test and euglycaemic–hyperinsulinaemic clamp performed with ³[H]glucose. Insulin sensitivity in skeletal muscle was measured as the insulin‐stimulated rate of total glucose disposal during the insulin clamp divided by steady‐state plasma insulin concentration (TGD/SSPI). Hepatic insulin resistance was measured as the product of basal hepatic glucose production and fasting plasma insulin concentration (HGP × FPI). Results Hepatic insulin resistance was strongly correlated (r = 0.68, P < 0.0001) with skeletal muscle insulin resistance. Thirty‐eight per cent of subjects had increased insulin resistance in both liver and skeletal muscle, while 39% were insulin sensitive in both skeletal muscle and liver. Twenty‐three per cent of subjects were discordant for muscle and hepatic insulin resistance (P < 0.0001). Subjects with increased skeletal muscle insulin resistance had a higher 2‐h plasma glucose concentration, greater incremental area under the plasma glucose concentration curve, lower fasting plasma insulin concentration and lower rate of basal hepatic glucose production compared with subjects with increased insulin resistance in liver. Conclusion In non‐diabetic subjects, insulin resistance in skeletal muscle is an important determinant of the fasting and 2‐h plasma glucose concentrations and strongly correlates with hepatic insulin resistance.     

Insulin resistance increases the risk of incident type 2 diabetes mellitus in patients with non‐alcoholic fatty liver disease

Aim

Type 2 diabetes mellitus (T2DM) is a major complication of patients with non‐alcoholic fatty liver disease (NAFLD). The aim of this retrospective study is to determine the risk factors for development of T2DM in patients with biopsy‐proven NAFLD.

Methods

One hundred and sixty two consecutive patients with biopsy‐proven NAFLD who received a 75‐g oral glucose tolerance test were enrolled as the total cohort. Among them, we analyzed 89 patients without T2DM diagnosed by oral glucose tolerance test to estimate the cumulative rate for development of T2DM as the follow‐up cohort.

Results

Of 162 patients, the glucose tolerance pattern were DM in 45 patients (27.8%), impaired glucose tolerance in 68 (42.0%), and normal glucose tolerance in 49 (30.2%). Patients with NAFL tended to be more likely to have normal glucose tolerance than those with non‐alcoholic steatohepatitis (NASH). The serum levels of pre‐ and post‐load insulin were significantly higher in the NASH group. Of 89 patients without T2DM, 13 patients newly developed T2DM during a follow‐up period of 5.2 years. The cumulative rate of T2DM incidence was 8.8% at the end of the 5th year and 23.4% at the end of the 10th year. Multivariate analysis identified homeostasis model of assessment – insulin resistance (≥3.85, hazard ratio 40.1, P = 0.033) as an independent risk factor for development of T2DM.

Conclusions

Patients with NASH have an underlying potential of glucose intolerance. In NAFLD patients, insulin resistance is the most important risk factor for the incidence of T2DM. Appropriate therapy against insulin resistance could be needed for patients with NAFLD to prevent development of T2DM.     

Safety and efficacy of insulin glargine (HOE 901) versus NPH insulin in combination with oral treatment in Type 2 diabetic patients

Aims A European, randomized, 29‐centre, open‐label study compared the safety and efficacy of two formulations of insulin glargine and neutral protamine Hagedorn (NPH) human insulin, in combination with oral agents, in patients with Type 2 diabetes mellitus (DM). Methods Two‐hundred‐and‐four patients with Type 2 DM, in whom oral treatment alone was inadequate, were randomized to insulin glargine with 30 µg/ml zinc [insulin glargine (30)], or insulin glargine with 80 µg/ml zinc [insulin glargine (80)] or NPH insulin subcutaneously once daily. Insulin was titrated to aim for fasting blood glucose (FBG) values between 4 and 7 mmol/l. All participants received oral therapy during the 3‐week titration phase and 1‐week maintenance phase of the trial. Results No differences between treatment groups were observed in adjusted mean fasting plasma glucose; significant decreases of 3.4 mmol/l, 3.5 mmol/l and 3.1 mmol/l were observed within the insulin glargine (30), insulin glargine (80) and NPH insulin groups, respectively (P < 0.0001 in each case). No differences between groups, but significant changes within groups, were observed in self‐monitored FBG, mean FBG, blood glucose profile, stability of FBG, nocturnal blood glucose, fasting serum C‐peptide, non‐esterified fatty acids, haemoglobin A_1c, fructosamine and fasting serum insulin. A significantly greater proportion of NPH insulin patients experienced symptomatic nocturnal hypoglycaemia (19.1 NPH group vs. 7.3% glargine groups; P = 0.0123). Both insulins were well tolerated; one patient in each group experienced an injection site reaction. Conclusions Insulin glargine is as safe and effective as NPH insulin given once daily and in this study caused fewer episodes of nocturnal hypoglycaemia. Diabet. Med. 20, 545–551 (2003)     

Ethnic Variation in the Association of Hypertension With Type 2 Diabetes

Lifestyle changes occurring with urbanization increase the prevalence of both type 2 diabetes mellitus (T2DM) and hypertension (HTN). Yemenites who have immigrated to Israel have demonstrated a dramatic increase in T2DM but the prevalence of HTN in diabetic Yemenites is unclear. In a cross‐sectional study, the authors evaluated the prevalence of HTN and lifestyle patterns in Israelis with T2DM of Yemenite (Y‐DM) and non‐Yemenite (NY‐DM) origin. Y‐DM (n=63) and NY‐DM (n=120) had similar age (63±7 vs 64±7 years, P=.5), diabetes duration, diet adherence, and exercise patterns. Y‐DM had a lower prevalence of HTN (63%) than NY‐DM (83%) (P<.01). Furthermore, Yemenite origin was independently associated with lower prevalence of HTN (odds ratio, 0.3; 95% confidence interval, 0.12–0.71). Blood pressure was well controlled with fewer antihypertensive medications in Y‐DM than NY‐DM (P<.01). Even though lifestyle patterns were similar in the two groups, Y‐DM had a lower prevalence of HTN compared with NY‐DM and required fewer antihypertensive medications.     

Effect of prandial treatment timing adjustment,based on continuous glucose monitoring,in patients with type 2 diabetes uncontrolled with once‐daily basal insulin: A randomized,phase IV study

Aims

To evaluate the glycaemic control achieved by prandial once‐daily insulin glulisine injection timing adjustment, based on a continuous glucose monitoring sensor, in comparison to once‐daily insulin glulisine injection before breakfast in patients with type 2 diabetes who are uncontrolled with once‐daily basal insulin glargine.

Materials and Methods

This was a 24‐week open‐label, randomized, controlled, multicentre trial. At the end of an 8‐week period of basal insulin optimization, patients with HbA1c ≥ 7.5% and FPG < 130 mg/dL were randomized (1:1) to either arm A (no sensor) or arm B (sensor) to receive 16‐week intensified prandial glulisine treatment. Patients in arm A received pre‐breakfast glulisine, and patients in arm B received glulisine before the meal with the highest glucose elevation based on sensor data. The primary outcome was mean HbA1c at week 24 and secondary outcomes included rates of hypoglycaemic events and insulin dosage.

Results

A total of 121 patients were randomized to arm A (n = 61) or arm B (n = 60). There was no difference in mean HbA1c at week 24 between arms A and B (8.5% ± 1.2% vs 8.4% ± 1.0%; P = .66). The prandial insulin glulisine dosage for arm A and arm B was 9.3 and 10.1 units, respectively (P = .39). The frequency of hypoglycaemic events did not differ between study arms (36.1% vs 51.7%; P = .08).

Conclusion

Using a CGM sensor to identify the meal with the highest glucose excursion and adjusting the timing of prandial insulin treatment did not show any advantage in terms of glycaemic control or safety in our patients.     

Effect of pioglitazone on insulin sensitivity,vascular function and cardiovascular inflammatory markers in insulin‐resistant non‐diabetic Asian Indians

Aims To determine the effects of pioglitazone (30 mg once daily for 16 weeks) on insulin sensitivity, insulin‐mediated vasodilation, vascular inflammatory markers, fat distribution and lipids in Asian Indians and Caucasians of European ancestry. Methods Cross‐sectional study. Eighteen non‐diabetic Asian Indians and 17 Caucasians of comparable age (34 ± 3 vs. 36 ± 3 years) and body mass index (26.0 ± 1.2 vs. 24.7 ± 1.0 kg/m²) had measurements of insulin sensitivity (M, insulin clamp at 6 pmol/kg per min), abdominal fat (computed tomographic scan at L4‐L5), endothelial‐dependent (reactive hyperaemia, RH) and ‐independent (0.4 mg sublingual nitroglycerin, TNG) vasodilation using brachial artery ultrasound before and after the 2‐h clamp at baseline and after pioglitazone therapy. Results Asian Indians were insulin resistant compared with Causasians during the baseline clamp (M = 25.6 ± 1.7 vs. 41.1 ± 2.2 µmol/kg per min, P < 0.0001) and improved significantly after pioglitazone (to 33.9 ± 1.7 µmol/kg per min, P < 0.001). Vasodilatory responses to RH and TNG were similar in Asian Indians and Caucasians at baseline and did not change. Insulin‐mediated vasodilation improved after pioglitazone in Asian Indians, but not in Caucasians, and correlated with the change in insulin sensitivity (r = 0.52, P = 0.03). C‐reactive protein (CRP) was higher in Asian Indians vs. Caucasians (1.6 ± 0.4 vs. 0.9 ± 0.2 mg/l) and was negatively correlated with insulin sensitivity (r = ?0.53, P = 0.02). In the Asian Indian group, CRP and plasminogen activator inhibitor‐1 decreased and adiponectin increased after pioglitazone, but there were no significant changes in total or visceral fat. Conclusions These results demonstrate that insulin‐resistant Asian Indians respond favourably to an insulin sensitizer with improvements in insulin sensitivity, cardiovascular and inflammatory risk markers, and vascular responses to insulin. These agents may have a role in decreasing the risk of diabetes and cardiovascular disease in this high‐risk population.     

Femoral–gluteal adiposity is not associated with insulin sensitivity in Type 1 diabetes

Aims To quantify and compare associations between femoral–gluteal adiposity and insulin sensitivity in adults with Type 1 diabetes mellitus with adults with normal glucose tolerance. Methods Individuals with Type 1 diabetes (n = 28) were recruited from the Pittsburgh Epidemiology of Diabetes Complication study, a 24‐year prospective study of childhood‐onset diabetes, and compared cross‐sectionally with individuals with normal glucose tolerance (n = 56) of similar age, sex and BMI. Insulin sensitivity was defined as whole‐body glucose disposal measured by hyperinsulinaemic–euglycaemic clamps. Adiposity was quantified by dual energy X‐ray absorptiometry. Results Individuals with Type 1 diabetes exhibited lower insulin sensitivity (5.8 vs. 8.2 mg min^?1 kg fat‐free mass^?1, P < 0.01), lower total fat mass (20.1 vs. 29.0 kg, P < 0.001) and lower proportional leg fat mass (36.0 vs.37.7%, P = 0.03), but similar proportional trunk fat (% trunk fat mass) compared with individuals with normal glucose tolerance. Overall, results from linear regression demonstrated that higher % leg fat mass (P < 0.01) and lower % trunk fat mass (P < 0.01) were independently associated with lower insulin sensitivity after adjustments for age, sex, height, total fat mass (kg) and diabetes status. Higher % leg fat mass was independently associated with higher insulin sensitivity in individuals with normal glucose tolerance (P < 0.01) after similar adjustment; significant associations were not observed in Type 1 diabetes. Conclusions Reduced insulin sensitivity is a prominent feature of Type 1 diabetes and is associated with total and abdominal adiposity. Compared with adults with normal glucose tolerance, leg fat mass does not show any positive association with insulin sensitivity in Type 1 diabetes.     

PREVIEW (Prevention of Diabetes Through Lifestyle Intervention and Population Studies in Europe and Around the World) study in children aged 10 to 17 years: Design,methods and baseline results

Insulin resistance (IR) in adolescence is associated with type 2 diabetes mellitus [T2DM]. The PREVIEW (Prevention of Diabetes Through Lifestyle Intervention and Population Studies in Europe and Around the World) study assessed the effectiveness of a high‐protein, low‐glycaemic‐index diet and a moderate‐protein, moderate‐glycaemic‐index diet to decrease IR in insulin‐resistant children who were overweight or obese. Inclusion criteria were age 10 to 17 years, homeostatic model assessment of IR (HOMA‐IR) ≥2.0 and overweight/obesity. In 126 children (mean ± SD age 13.6 ± 2.2 years, body mass index [BMI] z‐score 3.04 ± 0.66, HOMA‐IR 3.48 ± 2.28) anthropometrics, fat mass percentage (FM%), metabolic characteristics, physical activity, food intake and sleep were measured. Baseline characteristics did not differ between the groups. IR was higher in pubertal children with morbid obesity than in prepubertal children with morbid obesity (5.41 ± 1.86 vs 3.23 ± 1.86; P = .007) and prepubertal and pubertal children with overweight/obesity (vs 3.61 ± 1.60, P = .004, and vs 3.40 ± 1.50, P < .001, respectively). IR was associated with sex, Tanner stage, BMI z‐score and FM%. Fasting glucose concentrations were negatively associated with Baecke sport score (r = ?0.223, P = .025) and positively with daytime sleepiness (r = 0.280, P = .016) independent of sex, Tanner stage, BMI z‐score and FM%. In conclusion, IR was most severe in pubertal children with morbid obesity. The associations between fasting glucose concentration and Baecke sport score and sleepiness suggest these might be possible targets for diabetes prevention.     

Evaluation of proposed oral disposition index measures in relation to the actual disposition index

Aims While the disposition index provides a useful measure of B‐cell function, its calculation requires the performance of a frequently sampled intravenous glucose tolerance test (FSIVGTT). Recently, the demonstration of a hyperbolic relationship between indices of insulin secretion and insulin sensitivity derived from the oral glucose tolerance test (OGTT) has led to the introduction of two novel OGTT‐based measures of B‐cell function analogous to the disposition index: (i) the insulin secretion‐sensitivity index‐2 (ISSI‐2) (defined as the ratio of the area‐under‐the‐insulin‐curve to the area‐under‐the‐glucose curve, multiplied by the Matsuda index) and (ii) insulinogenic index (IGI)/fasting insulin. However, neither of these two measures has been directly compared with the disposition index. Methods Two hundred and thirteen non‐diabetic children (122 boys, 91 girls) underwent both OGTT and FSIVGTT, allowing for the calculation of ISSI‐2, IGI/fasting insulin and the disposition index. Results ISS1‐2 and IGI/fasting insulin were strongly correlated with each other (r = 0.82, P < 0.0001). Both measures correlated with the disposition index, with ISSI‐2 showing a modestly stronger association (ISSI‐2: r = 0.24, P = 0.0003; IGI/fasting insulin: r = 0.21, P = 0.0022). Standardized linear regression analyses confirmed that the relationship between log ISSI‐2 and the disposition index (standardized regression coefficient = 0.224, P = 0.001) was stronger than that between log IGI/fasting insulin and the disposition index (standardized regression coefficient = 0.166, P = 0.015). Conclusions The OGTT‐derived measures ISSI‐2 and IGI/fasting insulin exhibit modest correlations with the disposition index. These relationships require further assessment in other patient populations.