Diabetes and cancer: two diseases with obesity as a common risk factor

There is a growing body of evidence to support a connection between diabetes (predominantly type 2), obesity and cancer. Multiple meta‐analyses of epidemiological data show that people with diabetes are at increased risk of developing many different types of cancers, along with an increased risk of cancer mortality. Several pathophysiological mechanisms for this relationship have been postulated, including insulin resistance and hyperinsulinaemia, enhanced inflammatory processes, dysregulation of sex hormone production and hyperglycaemia. In addition to these potential mechanisms, a number of common risk factors, including obesity, may be behind the association between diabetes and cancer. Indeed, obesity is associated with an increased risk of cancer and diabetes. Abdominal adiposity has been shown to play a role in creating a systemic pro‐inflammatory environment, which could result in the development of both diabetes and cancer. Here, we examine the relationship between diabetes, obesity and cancer, and investigate the potential underlying causes of increased cancer risk in individuals with diabetes. Current treatment recommendations for reducing the overall disease burden are also explored and possible areas for future research are considered.     

Incidence and characteristics of lower limb amputations in people with diabetes

Aims To estimate the incidence, characteristics and potential causes of lower limb amputations in France. Methods Admissions with lower limb amputations were extracted from the 2003 French national hospital discharge database, which includes major diagnoses and procedures performed during hospital admissions. For each patient, diabetes was defined by its record in at least one admission with or without lower limb amputation in the 2002–2003 databases. Results In 2003, 17 551 admissions with lower limb amputation were recorded, involving 15 353 persons, which included 7955 people with diabetes. The crude incidence of lower limb amputation in people with diabetes was 378/100 000 (349 / 100 000 when excluding traumatic lower limb amputation). The sex and age standardized incidence was 12 times higher in people with than without diabetes (158 vs. 13/100 000). Renal complications and peripheral arterial disease and/or neuropathy were reported in, respectively, 30% and 95% of people with diabetes with lower limb amputation. Traumatic causes (excluding foot contusion) and bone diseases (excluding foot osteomyelitis) were reported in, respectively, 3% and 6% of people with diabetes and lower limb amputation, and were 5 and 13 times more frequent than in people without diabetes. Conclusions We provide a first national estimate of lower limb amputation in France. We highlight its major impact on people with diabetes and its close relationship with peripheral arterial disease/neuropathy and renal complications in the national hospital discharge database. We do not suggest the exclusion of traumatic causes when studying the epidemiology of lower limb amputation related to diabetes, as diabetes may contribute to amputation even when the first cause appears to be traumatic.     

Characteristics of adults with and without cystic fibrosis-related diabetes.

AIMS: The prevalence of diabetes in adults with cystic fibrosis (CF) approximates 25%, yet few studies have defined risk factors. We examined the association between biochemical and clinical factors and CF-related diabetes. METHODS: We performed a study in adults with CF in 2004 in Cambridgeshire, UK. Of 160 individuals, 51 had diabetes (cases) on the basis of medical history or screening using a 75-g oral glucose tolerance test, and 107 did not have diabetes (control subjects); two were excluded. We used logistic regression to model the cross-sectional association between potential risk factors and diabetes. RESULTS: The mean age was 26 (16-58) years, mean body mass index (BMI) was 21 (16-28) kg/m(2), and mean forced expiratory volume in 1 s was 60 +/- 24% (mean +/- sd). All of the cases and 88% of control subjects had pancreatic insufficiency. Cases did not differ from control subjects with respect to age, sex, body mass index, or dose of oral pancreatic enzymes. Cases were more likely to have low serum magnesium, haemoglobin, and pulmonary function, and higher serum gamma-glutamyl transferase (GGT) activity, plasma fibrinogen levels, erythrocyte sedimentation rate, use of oral corticosteroids, and number of CF-related complications. In multivariate analyses, GGT, previous organ transplantation, plasma fibrinogen and the presence of CF-related complications were independently associated with diabetes, after controlling for corticosteroid use. CONCLUSIONS: These data confirm the high prevalence of diabetes in adults with CF, and identify plasma fibrinogen and GGT, and organ transplantation as factors independently associated with CF-related diabetes. A prospective study would clarify the nature of these associations.     

Congenital anomalies in the offspring of women with type 1, type 2 and gestational diabetes.

AIM: To determine the frequency of major congenital anomalies in the offspring of women with gestational diabetes (GDM), classified according to their postpartum glucose tolerance status. METHODS: A prospective study of pregnancies in women with Type 1 diabetes (n = 221), Type 2 diabetes (n = 317) and GDM (n = 1822) between 1985 and 2000 (15 years). Congenital anomalies were detected by antenatal ultrasound or postnatal examination. RESULTS: The frequency of major congenital anomalies in the offspring was 5.9% (95% confidence interval (CI) 3.2-9.8) for women with Type 1 diabetes; 4.4% (95% CI 2.4-7.3) for women with Type 2 diabetes; and 1.4% (95% CI 0.9-2.0) for women with GDM. Two hundred and thirty-seven women with GDM (13%) had diabetes diagnosed on early (6-week) postpartum glucose tolerance testing. The frequency of major congenital anomalies in their offspring was 4.6% (95% CI 2.3-8.2), compared with 0.9% (95% CI 0.5-1.5) for the remainder of the GDM group (P < 0.0001). CONCLUSIONS: GDM is not a homogeneous group with regard to the risk of major congenital anomalies. In those with diabetes on early postpartum testing, who are likely to have had unrecognized Type 2 diabetes antedating their pregnancy, the rate of major congenital anomalies is the same as for women with established Type 1 or Type 2 diabetes. In the remainder of the GDM group, the rate does not differ from the non-diabetic background rate.     

血清镁与糖尿病及其并发症相关性的研究进展

镁是人体内重要的阳离子,参与体内多种代谢过程。既往研究表明低血镁与糖尿病的发生发展密切相关。近年来,血清镁水平与糖尿病并发症的相关性被广泛关注并成为研究热点。本文综述了近年来关于镁离子的分布与调节、血清镁与糖尿病及其并发症相关性及补镁临床应用的研究进展,以进一步理解血清镁在糖尿病及其并发症发病、进展机制中的作用,为临床治疗提供新思路。     

Relationship between heterogeneity of insulin responses and insulin resistance in normal subjects and patients with chemical diabetes

Summary Plasma insulin responses and insulin resistance were determined in 75 subjects, defined as having a normal, borderline abnormal, or abnormal oral glucose tolerance test (OGTT). Although considerable heterogeneity of insulin response existed, most patients with abnormal OGTT's had insulin responses greater than normal; none had insulin responses less than normal. The degree of insulin resistance also varied, but most patients with abnormal OGTT's were also abnormally insulin resistant. A significant correlation (r=0.64, p ±0.001) existed between insulin response and the degree of insulin resistance. However, when both variables were taken into consideration, the entire population could be divided into two groups. One group was characterized by both normal insulin responsiveness and sensitivity, the other by increased insulin response, associated with greater insulin resistance. Most patients with abnormal OGTT's fell into the latter group, but some had glucose intolerance without either an exaggerated insulin response or insulin resistance. These results suggest that true heterogeneity exists in patients with abnormal OGTT's.This work was supported in part by grants from the National Institutes of Health, #HL 08506 from the National Heart and Lung Institute and #RR-70 from the General Clinical Research Centers Branch, and from the Research Services of the Veterans AdministrationDr. Reaven is a Medical Investigator, Veterans AdministrationDr. Olefsky is a Clinical Investigator, Veterans Administration     

Performance evaluation and labeling comprehension of a new blood glucose monitoring system with integrated information management

Background

This study evaluated performance and product labeling of CONTOUR® USB, a new blood glucose monitoring system (BGMS) with integrated diabetes management software and a universal serial bus (USB) port, in the hands of untrained lay users and health care professionals (HCPs).

Method

Subjects and HCPs tested subject''s finger stick capillary blood in parallel using CONTOUR USB meters; deep finger stick blood was tested on a Yellow Springs Instruments (YSI) glucose analyzer for reference. Duplicate results by both subjects and HCPs were obtained to assess system precision. System accuracy was assessed according to International Organization for Standardization (ISO) 15197:2003 guidelines [within ±15 mg/dl of mean YSI results (samples <75 mg/dl) and ±20% (samples ≥75 mg/dl)]. Clinical accuracy was determined by Parkes error grid analysis. Subject labeling comprehension was assessed by HCP ratings of subject proficiency. Key system features and ease-of-use were evaluated by subject questionnaires.

Results

All subjects who completed the study (N = 74) successfully performed blood glucose measurements, connected the meter to a laptop computer, and used key features of the system. The system was accurate; 98.6% (146/148) of subject results and 96.6% (143/148) of HCP results exceeded ISO 15197:2003 criteria. All subject and HCP results were clinically accurate (97.3%; zone A) or associated with benign errors (2.7%; zone B). The majority of subjects rated features of the BGMS as “very good” or “excellent.”

Conclusions

CONTOUR USB exceeded ISO 15197:2003 system performance criteria in the hands of untrained lay users. Subjects understood the product labeling, found the system easy to use, and successfully performed blood glucose testing.     

Prevalence of diabetes mellitus and impaired glucose tolerance in parents of women with gestational diabetes

Summary Nuclear families of non-insulin-dependent diabetic (NIDDM) patients are uncommon, as usually one or both parents have died. In order to aid identification of complete nuclear families, we have ascertained the disease process at a younger age by studying subjects with previous gestational diabetes. One hundred women who had had gestational diabetes, age (±SD) 38 (6) years, were screened by fasting plasma glucose (fpg). Sixty-one were found to have either fasting hyperglycaemia (5.5fpg<7.8 mmol/l) or diabetes. Of these women 35 had both parents alive and the parents of 14 of these women agreed to the assessment of their metabolism by a continuous infusion of glucose with model assessment (CIGMA). Seven probands had impaired glucose tolerance (IGT) and seven were diabetic. They were age 35 (4) years and had body mass index (BMI) 26 (5) kg/m². The parents were aged 62 (6) years and had BMI 29 (6) kg/m² and their affection status was defined as presence of glucose intolerance (fpg or post-infusion achieved plasma glucose level >2 SD of an age and obesity matched population). In the 14 families, five probands (36%) had neither parent affected, six (43%) had one parent affected and three (21%) had both parents affected. Only three probands had a parent with diabetes as defined by World Health Organisation criteria. We concludes that the study of women who have had gestational diabetes allows detection of probands with diabetes or impaired glucose tolerance, who have both parents available for study. A substantial proportion had neither parent affected with impaired glucose tolerance or diabetes, similar to the nuclear families of NIDDM patients. The results are in accord with studies of nuclear families of NIDDM patients in suggesting polygenic inheritance or environmental influences rather than autosomal dominant inheritance with high penetrance.Abbreviations IGT Impaired glucose tolerance - GTT glucose tolerance test - NIDDM non-insulin-dependent diabetes mellitus - fpg fasting plasma glucose - apg achieved plasma glucose - CIGMA continuous infusion of glucose test - BMI body mass index     

Insulin dependent diabetes: A comparison of families with single and multiple affected siblings

Summary Families (n = 14) with more than 1 sibling with insulin dependent diabetes were matched with families of similar size and age distribution containing only 1 affected child. The distribution of HLA haplotypes, age of onset of disease, and seasonal onset of disease were compared in the two groups. The data are not consistent with the hypothesis of a single autosomal recessive gene linked to the HLA region. The data do not permit a choice between other current hypotheses although they are compatible with the theory of 2 genes linked to the HLA region, acting additively, and requiring interaction either with environmental factors or other disease susceptibility genes. Diabetic children in the multiplex and simplex families did not differ in the month of onset of symptoms nor in the age at diagnosis although three multiplex pedigrees in which diabetes developed in all affected children before the age of 6 years were identified.     

Treatment of patients with non-insulin-dependent diabetes mellitus: diabetic control and insulin secretion and action after different treatment modalities

In order to define the relationship between treatment-induced changes in diabetic control and improvement in in vivo insulin-stimulated glucose utilization (insulin clamp technique) 30 patients with non-insulin-dependent diabetes mellitus (NIDDM) were treated with either insulin, glipizide or diet alone, depending on their initial weight. Fasting plasma glucose concentrations fell from 16.3 +/- 1.2, 15.9 +/- 1.0, and 16.3 +/- 1.0 mmol/l, (mean +/- SE) to 6.3 +/- 0.5, 11.6 +/- 0.6, and 13.4 +/- 1.6 mmol/l, after insulin, glipizide and weight reduction, respectively. These changes in fasting plasma glucose concentration were associated with an improvement in insulin-stimulated glucose uptake, which increased by 69% after insulin, 45% after glipizide, and 72% after weight reduction. Thus, the improvement in insulin action was comparable in the three different groups of patients following each therapeutic intervention, and appeared to be unrelated to the fall in plasma glucose concentration. These results appear to suggest that the ability of any specific treatment to improve diabetic control can vary independently of its effect on in vivo insulin-stimulated glucose utilization.     

Serious hand sepsis and diabetes mellitus: specific tropical syndrome with western counterparts

Infection in the extremities of diabetic patients most commonly involves the feet and, at least in western societies, is often associated with chronic complications of diabetes. Severe hand infection, often culminating in amputation and even death, is, however, well-described in tropical countries, where it may not be associated with any evidence of neuropathy or arterial insufficiency. Similar cases are described in the western literature but are more often associated with more severe antecedent trauma. The literature describing hand sepsis in diabetic patients both in tropical and in western practice is reviewed and we draw some conclusions about pathogenesis and treatment from the literature and from original data documenting the varying experience of hand sepsis in diabetic practice throughout Africa. © 1998 John Wiley & Sons, Ltd.     

Testing for monogenic diabetes among children and adolescents with antibody‐negative clinically defined Type 1 diabetes

Aims Monogenic diabetes is frequently misdiagnosed as Type 1 diabetes. We aimed to screen for undiagnosed monogenic diabetes in a cohort of children who had a clinical diagnosis of Type 1 diabetes but were pancreatic autoantibody‐negative. Methods We studied 252 patients diagnosed clinically with Type 1 diabetes between 6 months and 17 years of age. Pancreatic autoantibodies [islet cell autoantibodies (ICA), glutamic acid decarboxylase antibodies (GADA) and/or insulinoma‐associated antigen‐2 antibodies (IA2A)] were absent in 25 cases (9.9%). The most frequent genes involved in monogenic diabetes [KCNJ11 and INS for neonatal diabetes and HNF1A and HNF4A for maturity‐onset diabetes of the young (MODY)] were directly sequenced. Results Two of the 25 (8%) antibody‐negative patients had de novo heterozygous mutations in INS; c.94G>A (G32S) and c.265C>T (R89C). The two patients presented with non‐ketotic hyperglycaemia at 8 and 11 months of age. In contrast, the four antibody‐positive patients who presented at a similar age (6–12 months) had a more severe metabolic derangement, manifested as ketosis in all four cases, with ketoacidosis in two. At ages 15 and 5 years, both INS mutation patients were prescribed a replacement dose of insulin with good glycaemic control [glycated haemoglobin (HbA_1c) 7.0 and 7.2%]. No mutations were found in KCNJ11, HNF1A or HNF4A. Conclusions The identification of patients with monogenic diabetes from children with clinically defined Type 1 diabetes may be helped by clinical criteria including the absence of pancreatic autoantibodies.     

The effect of initial therapy with the fixed-dose combination of sitagliptin and metformin compared with metformin monotherapy in patients with type 2 diabetes mellitus

Aims: This study was conducted to compare the glycaemic efficacy and safety of initial combination therapy with the fixed‐dose combination of sitagliptin and metformin versus metformin monotherapy in drug‐naive patients with type 2 diabetes. Methods: This double‐blind study (18‐week Phase A and 26‐week Phase B) randomized 1250 drug‐naÏve patients with type 2 diabetes [mean baseline haemoglobin A1c (HbA1c) 9.9%] to sitagliptin/metformin 50/500 mg bid or metformin 500 mg bid (uptitrated over 4 weeks to achieve maximum doses of sitagliptin/metformin 50/1000 mg bid or metformin 1000 bid). Results of the primary efficacy endpoint (mean HbA1c reductions from baseline at the end of Phase A) are reported herein. Results: At week 18, mean change from baseline HbA1c was ?2.4% for sitagliptin/metformin FDC and ?1.8% for metformin monotherapy (p < 0.001); more patients treated with sitagliptin/metformin FDC had an HbA1c value <7% (p < 0.001) versus metformin monotherapy. Changes in fasting plasma glucose were significantly greater with sitagliptin/metformin FDC (?3.8 mmol/l) versus metformin monotherapy (?3.0 mmol/l; p < 0.001). Homeostasis model assessment of β‐cell function (HOMA‐β) and fasting proinsulin/insulin ratio were significantly improved with sitagliptin/metformin FDC versus metformin monotherapy. Baseline body weight was reduced by 1.6 kg in each group. Both treatments were generally well tolerated with a low and similar incidence of hypoglycaemia. Abdominal pain (1.1 and 3.9%; p = 0.002) and diarrhoea (12.0 and 16.6%; p = 0.021) occurred significantly less with sitagliptin/metformin FDC versus metformin monotherapy; the incidence of nausea and vomiting was similar in both groups. Conclusion: Compared with metformin monotherapy, initial treatment with sitagliptin/metformin FDC provided superior glycaemic improvement with a similar degree of weight loss and lower incidences of abdominal pain and diarrhoea.     

Treatment and prevention of severe hypoglycaemia in people with diabetes: Current and new formulations of glucagon

Some therapies for diabetes increase the risk of hypoglycaemia, in particular all insulins and insulin secretagogues, including the glinides and sulfonylureas. Hypoglycaemia remains a major limiting factor to successful glycaemic management, despite the availability of prevention options such as insulin analogues, continuous glucose monitoring, insulin pumps, and dogs that have been trained to detect hypoglycaemia. Non-severe (self-treated) and severe (requiring assistance for recovery) hypoglycaemia rates are higher in people with type 1 diabetes, but those with insulin-treated type 2 diabetes are also at risk. Education and regular review are essential between people with diabetes and their caregivers and healthcare professionals about symptoms, prevention and treatment. Awareness of the potential dangers of hypoglycaemia is fundamental to the optimal management of diabetes. When therapy is intensified to achieve glycaemic targets, it is important that people at risk of severe hypoglycaemia, and particularly their caregivers, have ready access to effective treatment for hypoglycaemia emergencies. The current and potential formulations of glucagon available for treatment of severe hypoglycaemia are reviewed.