Allan Vaag

Diabetes Patients Requiring Glucose-Lowering Therapy and Nondiabetics With a Prior Myocardial Infarction Carry the Same Cardiovascular Risk A Population Study of 3.3 Million People

Background— Previous studies reveal major differences in the estimated cardiovascular risk in diabetes mellitus, including uncertainty about the risk in young patients. Therefore, large studies of well-defined populations are needed. Methods and Results— All residents in Denmark ≥30 years of age were followed up for 5 years (1997 to 2002) by individual-level linkage of nationwide registers. Diabetes patients receiving glucose-lowering medications and nondiabetics with and without a prior myocardial infarction were compared. At baseline, 71 801 (2.2%) had diabetes mellitus and 79 575 (2.4%) had a prior myocardial infarction. Regardless of age, age-adjusted Cox proportional-hazard ratios for cardiovascular death were 2.42 (95% confidence interval [CI], 2.35 to 2.49) in men with diabetes mellitus without a prior myocardial infarction and 2.44 (95% CI, 2.39 to 2.49) in nondiabetic men with a prior myocardial infarction (P=0.60), with nondiabetics without a prior myocardial infarction as the reference. Results for women were 2.45 (95% CI, 2.38 to 2.51) and 2.62 (95% CI, 2.55 to 2.69) (P=0.001), respectively. For the composite of myocardial infarction, stroke, and cardiovascular death, the hazard ratios in men with diabetes only were 2.32 (95% CI, 2.27 to 2.38) and 2.48 (95% CI, 2.43 to 2.54) in those with a prior myocardial infarction only (P=0.001). Results for women were 2.48 (95% CI, 2.43 to 2.54) and 2.71 (95% CI, 2.65 to 2.78) (P=0.001), respectively. Risks were similar for both diabetes types. Analyses with adjustments for comorbidity, socioeconomic status, and prophylactic medical treatment showed similar results, and propensity score–based matched-pair analyses supported these findings. Conclusions— Patients requiring glucose-lowering therapy who were ≥30 years of age exhibited a cardiovascular risk comparable to nondiabetics with a prior myocardial infarction, regardless of sex and diabetes type. Therefore, requirement for glucose-lowering therapy should prompt intensive prophylactic treatment for cardiovascular diseases.

Genetic variant near IRS1 is associated with type 2 diabetes, insulin resistance and hyperinsulinemia

Genome-wide association studies have identified common variants that only partially explain the genetic risk for type 2 diabetes (T2D). Using genome-wide association data from 1,376 French individuals, we identified 16,360 SNPs nominally associated with T2D and studied these SNPs in an independent sample of 4,977 French individuals. We then selected the 28 best hits for replication in 7,698 Danish subjects and identified 4 SNPs showing strong association with T2D, one of which (rs2943641, P = 9.3 × 10−12, OR = 1.19) was located adjacent to the insulin receptor substrate 1 gene (IRS1). Unlike previously reported T2D risk loci, which predominantly associate with impaired beta cell function, the C allele of rs2943641 was associated with insulin resistance and hyperinsulinemia in 14,358 French, Danish and Finnish participants from population-based cohorts; this allele was also associated with reduced basal levels of IRS1 protein and decreased insulin induction of IRS1-associated phosphatidylinositol-3-OH kinase activity in human skeletal muscle biopsies.

Prevalence of micro- and macroalbuminuria, arterial hypertension, retinopathy and large vessel disease in European type 2 (non-insulin-dependent) diabetic patients.

SummaryThe prevalence of micro- and macroalbuminuria was determined in Type 2 (non-insulin-dependent) diabetic patients, less than 76 years of age, attending a diabetic clinic during 1987. All eligible patients (n=557) were asked to collect a 24-h urine sample for quantitative albumin analysis. Urine collections were obtained in 296 males and 253 females (96%). Normoalbuminuria were defined as urinary albumin excretion≤30 mg/24 h (n=323), microalbuminuria as 31–299 mg/24 h (n=151), and macroalbuminuria as ≥300 mg/ 24 h (n=75). The prevalence of macroalbuminuria was significantly higher in males (20%) than in females (6%), while the prevalence of microalbuminuria was almost identical in males (26%) and females (29%). The prevalence of arterial hypertension increased with increased albuminuria, being 48%, 68%, and 85% in patients with normoalbuminuria, microalbuminuria, and macroalbuminuria respectively. Prevalence of proliferative retinopathy rose with increasing albuminuria, being 2%, 5% and 12% in patients with normoalbuminuria, microalbuminuria, and macroalbuminuria respectively. Prevalence of coronary heart disease, based on Minnesota coded electrocardiograms, was more frequent in patients with macroalbuminuria (46%) compared to patients with microalbuminuria (26%) and patients with normoalbuminuria (22%). Foot ulcers were more frequent in micro- and macroalbuminuric patients, being 13% and 25%, respectively, compared to 5% in patients with normoalbuminuria. This cross-sectional study has revealed a high prevalence of microalbuminuria (27%) and macroalbuminuria (14%) in Type 2 diabetic patients. Patients with raised urinary albumin excretion are characterized by obesity, elevated haemoglobin Alc, increased frequency of arterial hypertension, proliferative retinopathy, coronary heart disease and foot ulcers. Thus, these findings suggest that urinary excretion of albumin should be monitored routinely in patients with Type 2 diabetes.

‘Mortality and cardiovascular risk associated with different insulin secretagogues compared with metformin in type 2 diabetes, with or without a previous myocardial infarction: a nationwide study’

AIMS The impact of insulin secretagogues (ISs) on long-term major clinical outcomes in type 2 diabetes remains unclear. We examined mortality and cardiovascular risk associated with all available ISs compared with metformin in a nationwide study. METHODS AND RESULTS All Danish residents >20 years, initiating single-agent ISs or metformin between 1997 and 2006 were followed for up to 9 years (median 3.3 years) by individual-level linkage of nationwide registers. All-cause mortality, cardiovascular mortality, and the composite of myocardial infarction (MI), stroke, and cardiovascular mortality associated with individual ISs were investigated in patients with or without previous MI by multivariable Cox proportional-hazard analyses including propensity analyses. A total of 107 806 subjects were included, of whom 9607 had previous MI. Compared with metformin, glimepiride (hazard ratios and 95% confidence intervals): 1.32 (1.24-1.40), glibenclamide: 1.19 (1.11-1.28), glipizide: 1.27 (1.17-1.38), and tolbutamide: 1.28 (1.17-1.39) were associated with increased all-cause mortality in patients without previous MI. The corresponding results for patients with previous MI were as follows: glimepiride: 1.30 (1.11-1.44), glibenclamide: 1.47 (1.22-1.76), glipizide: 1.53 (1.23-1.89), and tolbutamide: 1.47 (1.17-1.84). Results for gliclazide [1.05 (0.94-1.16) and 0.90 (0.68-1.20)] and repaglinide and [0.97 (0.81-1.15) and 1.29 (0.86-1.94)] were not statistically different from metformin in both patients without and with previous MI, respectively. Results were similar for cardiovascular mortality and for the composite endpoint. CONCLUSION Monotherapy with the most used ISs, including glimepiride, glibenclamide, glipizide, and tolbutamide, seems to be associated with increased mortality and cardiovascular risk compared with metformin. Gliclazide and repaglinide appear to be associated with a lower risk than other ISs.

Decreased insulin activation of glycogen synthase in skeletal muscles in young nonobese Caucasian first-degree relatives of patients with non-insulin-dependent diabetes mellitus.

Insulin resistance in non-insulin-dependent diabetes is associated with a defective insulin activation of the enzyme glycogen synthase in skeletal muscles. To investigate whether this may be a primary defect, we studied 20 young (25 +/- 1 yr) Caucasian first-degree relatives (children) of patients with non-insulin-dependent diabetes, and 20 matched controls without a family history of diabetes. Relatives and controls had a normal oral glucose tolerance, and were studied by means of the euglycemic hyperinsulinemic clamp technique, which included performance of indirect calorimetry and muscle biopsies. Insulin-stimulated glucose disposal was decreased in the relatives (9.2 +/- 0.6 vs 11.5 +/- 0.5 mg/kg fat-free mass per (FFM) min, P less than 0.02), and was due to a decreased rate of insulin-stimulated nonoxidative glucose metabolism (5.0 +/- 0.5 vs 7.5 +/- 0.4 mg/kg fat-free mass per min, P less than 0.001). The insulin-stimulated, fractional glycogen synthase activity (0.1/10 mmol liter glucose-6-phosphate) was decreased in the relatives (46.9 +/- 2.3 vs 56.4 +/- 3.2%, P less than 0.01), and there was a significant correlation between insulin-stimulated, fractional glycogen synthase activity and nonoxidative glucose metabolism in relatives (r = 0.76, P less than 0.001) and controls (r = 0.63, P less than 0.01). Furthermore, the insulin-stimulated increase in muscle glycogen content over basal values was lower in the relatives (13 +/- 25 vs 46 +/- 9 mmol/kg dry wt, P = 0.05). We conclude that the defect in insulin activation of muscle glycogen synthase may be a primary, possibly genetically determined, defect that contributes to the development of non-insulin-dependent diabetes.

Sustained Effects of Interleukin-1 Receptor Antagonist Treatment in Type 2 Diabetes

OBJECTIVE Interleukin (IL)-1 impairs insulin secretion and induces β-cell apoptosis. Pancreatic β-cell IL-1 expression is increased and interleukin-1 receptor antagonist (IL-1Ra) expression reduced in patients with type 2 diabetes. Treatment with recombinant IL-1Ra improves glycemia and β-cell function and reduces inflammatory markers in patients with type 2 diabetes. Here we investigated the durability of these responses. RESEARCH DESIGN AND METHODS Among 70 ambulatory patients who had type 2 diabetes, A1C >7.5%, and BMI >27 kg/m2 and were randomly assigned to receive 13 weeks of anakinra, a recombinant human IL-1Ra, or placebo, 67 completed treatment and were included in this double-blind 39-week follow-up study. Primary outcome was change in β-cell function after anakinra withdrawal. Analysis was done by intention to treat. RESULTS Thirty-nine weeks after anakinra withdrawal, the proinsulin-to-insulin (PI/I) ratio but not stimulated C-peptide remained improved (by −0.07 [95% CI −0.14 to −0.02], P = 0.011) compared with values in placebo-treated patients. Interestingly, a subgroup characterized by genetically determined low baseline IL-1Ra serum levels maintained the improved stimulated C-peptide obtained by 13 weeks of IL-1Ra treatment. Reductions in C-reactive protein (−3.2 mg/l [−6.2 to −1.1], P = 0.014) and in IL-6 (−1.4 ng/l [−2.6 to −0.3], P = 0.036) were maintained until the end of study. CONCLUSIONS IL-1 blockade with anakinra induces improvement of the PI/I ratio and markers of systemic inflammation lasting 39 weeks after treatment withdrawal.

Intensive glycaemic control for patients with type 2 diabetes: systematic review with meta-analysis and trial sequential analysis of randomised clinical trials

Objective To assess the effect of targeting intensive glycaemic control versus conventional glycaemic control on all cause mortality and cardiovascular mortality, non-fatal myocardial infarction, microvascular complications, and severe hypoglycaemia in patients with type 2 diabetes. Design Systematic review with meta-analyses and trial sequential analyses of randomised trials. Data sources Cochrane Library, Medline, Embase, Science Citation Index Expanded, LILACS, and CINAHL to December 2010; hand search of reference lists and conference proceedings; contacts with authors, relevant pharmaceutical companies, and the US Food and Drug Administration. Study selection Randomised clinical trials comparing targeted intensive glycaemic control with conventional glycaemic control in patients with type 2 diabetes. Published and unpublished trials in all languages were included, irrespective of predefined outcomes. Data extraction Two reviewers independently assessed studies for inclusion and extracted data related to study methods, interventions, outcomes, risk of bias, and adverse events. Risk ratios with 95% confidence intervals were estimated with fixed and random effects models. Results Fourteen clinical trials that randomised 28 614 participants with type 2 diabetes (15 269 to intensive control and 13 345 to conventional control) were included. Intensive glycaemic control did not significantly affect the relative risks of all cause (1.02, 95% confidence interval 0.91 to 1.13; 28 359 participants, 12 trials) or cardiovascular mortality (1.11, 0.92 to 1.35; 28 359 participants, 12 trials). Trial sequential analyses rejected a relative risk reduction above 10% for all cause mortality and showed insufficient data on cardiovascular mortality. The risk of non-fatal myocardial infarction may be reduced (relative risk 0.85, 0.76 to 0.95; P=0.004; 28 111 participants, 8 trials), but this finding was not confirmed in trial sequential analysis. Intensive glycaemic control showed a reduction of the relative risks for the composite microvascular outcome (0.88, 0.79 to 0.97; P=0.01; 25 600 participants, 3 trials) and retinopathy (0.80, 0.67 to 0.94; P=0.009; 10 793 participants, 7 trials), but trial sequential analyses showed that sufficient evidence had not yet been reached. The estimate of an effect on the risk of nephropathy (relative risk 0.83, 0.64 to 1.06; 27 769 participants, 8 trials) was not statistically significant. The risk of severe hypoglycaemia was significantly increased when intensive glycaemic control was targeted (relative risk 2.39, 1.71 to 3.34; 27 844 participants, 9 trials); trial sequential analysis supported a 30% increased relative risk of severe hypoglycaemia. Conclusion Intensive glycaemic control does not seem to reduce all cause mortality in patients with type 2 diabetes. Data available from randomised clinical trials remain insufficient to prove or refute a relative risk reduction for cardiovascular mortality, non-fatal myocardial infarction, composite microvascular complications, or retinopathy at a magnitude of 10%. Intensive glycaemic control increases the relative risk of severe hypoglycaemia by 30%.

Metabolic and Vascular Effects of Tumor Necrosis Factor-α Blockade with Etanercept in Obese Patients with Type 2 Diabetes

Objective: The pro-inflammatory cytokine tumor necrosis factor-α (TNF-α) impairs insulin action in insulin-sensitive tissues, such as fat, muscle and endothelium, and causes endothelial dysfunction. We hypothesized that TNF-α blockade with etanercept could reverse vascular and metabolic insulin resistance. Method and Results: Twenty obese patients with type 2 diabetes were randomized to etanercept treatment (25 mg subcutaneously twice weekly for 4 weeks) or used as controls in an open parallel study. Forearm blood flow and glucose uptake were measured during intra-arterial infusions of serotonin, sodium nitroprusside and insulin co-infused with serotonin. β-Cell function was assessed with oral and intra-venous glucose tolerance tests and whole-body insulin sensitivity by hyperinsulinemic euglycemic clamps. Plasma levels of C-reactive protein and interleukin-6 decreased significantly with etanercept (C-reactive protein from 9.9 ± 3.1 to 4.8 ± 1.4 mg l–1, p = 0.04; interleukin-6 from 3.1 ± 0.4 to 1.9 ± 0.2 ng l–1, p = 0.03). Vasodilatory responses to serotonin and sodium nitroprusside infusions remained unchanged. Insulin effect on vasodilatation and on whole-body and forearm glucose uptake remained unchanged as well. β-Cell function tended to improve. Conclusion: Although short-term etanercept treatment had a significant beneficial effect on systemic inflammatory markers, no improvement of vascular or metabolic insulin sensitivity was observed.

Impact of short‐term high‐fat feeding on glucose and insulin metabolism in young healthy men

A high‐fat, high‐calorie diet is associated with obesity and type 2 diabetes. However, the relative contribution of metabolic defects to the development of hyperglycaemia and type 2 diabetes is controversial. Accumulation of excess fat in muscle and adipose tissue in insulin resistance and type 2 diabetes may be linked with defective mitochondrial oxidative phosphorylation. The aim of the current study was to investigate acute effects of short‐term fat overfeeding on glucose and insulin metabolism in young men. We studied the effects of 5 days’ high‐fat (60% energy) overfeeding (+50%) versus a control diet on hepatic and peripheral insulin action by a hyperinsulinaemic euglycaemic clamp, muscle mitochondrial function by 31P magnetic resonance spectroscopy, and gene expression by qrt‐PCR and microarray in 26 young men. Hepatic glucose production and fasting glucose levels increased significantly in response to overfeeding. However, peripheral insulin action, muscle mitochondrial function, and general and specific oxidative phosphorylation gene expression were unaffected by high‐fat feeding. Insulin secretion increased appropriately to compensate for hepatic, and not for peripheral, insulin resistance. High‐fat feeding increased fasting levels of plasma adiponectin, leptin and gastric inhibitory peptide (GIP). High‐fat overfeeding increases fasting glucose levels due to increased hepatic glucose production. The increased insulin secretion may compensate for hepatic insulin resistance possibly mediated by elevated GIP secretion. Increased insulin secretion precedes the development of peripheral insulin resistance, mitochondrial dysfunction and obesity in response to overfeeding, suggesting a role for insulin per se as well GIP, in the development of peripheral insulin resistance and obesity.

Insulin secretion, insulin action, and hepatic glucose production in identical twins discordant for non-insulin-dependent diabetes mellitus.

12 identical twin pairs discordant for non-insulin-dependent diabetes mellitus (NIDDM) were studied for insulin sensitivity (euglycemic insulin clamp, 40 mU/m2 per min), hepatic glucose production (HGP, [3-3H]glucose infusion), and insulin secretion (oral glucose tolerance test and hyperglycemic [12 mM] clamp, including glucagon administration). Five of the nondiabetic twins had normal and seven had impaired glucose tolerance. 13 matched, healthy subjects without a family history of diabetes were included as control subjects. The NIDDM twins were more obese compared with their non-diabetic co-twins. The nondiabetic twins were insulin resistant and had a delayed insulin and C-peptide response during oral glucose tolerance tests compared with controls. Furthermore, the nondiabetic twins had a decreased first-phase insulin response and a decreased maximal insulin secretion capacity during hyperglycemic clamping and intravenous glucagon administration. Nondiabetic twins and controls had similar rates of HGP. Compared with both nondiabetic twins and controls, the NIDDM twins had an elevated basal rate of HGP, a further decreased insulin sensitivity, and a further impaired insulin secretion pattern as determined by all tests. In conclusion, defects of both in vivo insulin secretion and insulin action are present in non- and possibly prediabetic twins who possess the necessary NIDDM susceptibility genes. However, all defects of both insulin secretion and glucose metabolism are expressed quantitatively more severely in their identical co-twins with overt NIDDM.