Management of type 2 diabetes in geriatric patients.

The International Diabetes Federation (IDF) indicates age above 45 years as a major risk factor for diabetes and predicts that the number of persons with the disease, which currently stands at 190 million, will double by the year 2025. Several recent trials suggest that tighter glucose control reduces long-term complications in diabetic patients; however, outcomes of tight blood sugar control in the elderly are not known. Nevertheless, the principles of management of type 2 diabetes in the elderly are not different from those in middle-aged patients. There are several reasons to keep glucose control on target, also in the elderly; nonetheless, it should be considered that the risk of hypoglycemia is more deleterious in the elderly and should be avoided. The old and more recent oral glucose-lowering agents, along with the newer types of insulin, will be discussed in this review.

Association of the Q121 variant of ENPP1 gene with decreased kidney function among patients with type 2 diabetes.

BACKGROUND: Insulin resistance has a role in diabetic kidney complications. The K121Q (lysine to glutamine substitution at amino acid 121, encoded by single-nucleotide polymorphism rs1044498) variant of the ectonucleotide pyrophosphatase/phosphodiesterase gene (ENPP1) has been associated with insulin resistance and related vascular complications in patients with type 2 diabetes (T2D) in many, although not all, studies. This study investigated whether the ENPP1 Q121 variant modulates the risk of decreased glomerular filtration rate (GFR) in patients with T2D. STUDY DESIGN: Cross-sectional study. SETTING & PARTICIPANTS: 2 diabetes units from Italy (in Gargano and Padua) and 1 from the United States (Boston, MA) recruited a total of 1,392 patients with T2D. PREDICTOR: The ENPP1 Q121 variant. MEASUREMENTS: Estimated GFR from serum creatinine, urinary albumin excretion, blood pressure, hemoglobin A(1c), triglycerides, total cholesterol, and high-density lipoprotein cholesterol. OUTCOMES: Decreased GFRs (ie, estimated GFR <60 mL/min/1.73 m(2)). RESULTS: In the Gargano and Boston populations, according to the dominant model of inheritance, Q121 carriers (ie, individual with either KQ or QQ alleles) had an increased risk of decreased GFR: odds ratios (ORs) of 1.69 (95% confidence interval [CI], 1.1 to 2.6) and 1.50 (95% CI, 1.0 to 2.2), respectively. In the Padua set, the association was in the same direction, but did not reach formal statistical significance (OR, 1.77; 95% CI, 0.7 to 4.5). When the 3 studies were pooled, Q121 carriers showed an increased risk of decreased GFR (OR, 1.58; 95% CI, 1.2 to 2.1; P = 0.002). Also, pooled mean differences in absolute GFRs were different across genotype groups, with Q121 carriers showing lower GFRs compared with KK individuals (P = 0.04). LIMITATIONS: P values not approaching a genome-wide level of significance. CONCLUSIONS: Our data suggest that patients with T2D carrying the ENPP1 Q121 variant are at increased risk of decreased GFR.

Cigarette smoking is associated with low glomerular filtration rate in male patients with type 2 diabetes.

OBJECTIVE: The relationship between cigarette smoking and renal dysfunction in diabetes has predominantly been documented in patients with type 1 diabetes. The aim of the present study was to explore the relationship between cigarette smoking and glomerular filtration rate (GFR) in a large cross-sectional study carried out in male subjects with type 2 diabetes. The role of metabolic syndrome in modulating this relationship was also investigated. RESEARCH DESIGN AND METHODS: One hundred fifty-eight current smokers and 158 never smokers with type 2 diabetes were consecutively recruited. Low GFR was defined as GFR <60 ml/min per 1.73 m(2). RESULTS: The proportion of patients affected by low GFR was significantly higher in current smokers (20.9 vs. 12.0%, P = 0.03). The adjusted risk (odds ratio [OR]) of low GFR in current smokers was 2.20 (95% CI 1.14-4.26, P = 0.02) and markedly higher in patients from the first tertile of disease duration (4.27 [1.26-14.40], P = 0.02). When metabolic syndrome was added to the statistical model exploring the relationship between smoking and low GFR, the risk of low GFR showed a small change, although it did not become any more significant (1.84 [0.98-3.45], P = 0.06). Current smokers showed even higher free oxygen radical test unit values (560.0 +/- 91.5 vs. 442.7 +/- 87.2, P < 0.0001). CONCLUSIONS: In a large population of male patients with type 2 diabetes, the risk of low GFR is markedly enhanced by smoking and is at least partially mediated by metabolic syndrome.

The K121Q polymorphism of the ENPP1/PC-1 gene is associated with insulin resistance/atherogenic phenotypes, including earlier onset of type 2 diabetes and myocardial infarction.

Insulin resistance (IR) is pathogenic for type 2 diabetes and coronary artery disease (CAD). The K121Q polymorphism of the ENPP1/PC-1 gene is associated with IR. Our aim was to investigate the role of the 121Q variant on the risk of type 2 diabetes and CAD. Nondiabetic control subjects (n = 638), type 2 diabetic patients without CAD (n = 535), and type 2 diabetic patients with CAD (n = 434) from Italy and the U.S. were studied. The proportion of 121Q carriers progressively increased in the three groups (27.4, 28.8, and 33.2%, respectively; adjusted P value = 0.027). Among diabetic patients (n = 969), 121Q carriers had an increased risk of developing type 2 diabetes before the age of 65 years (adjusted odds ratio [OR] 2.26, 95% CI 1.26-4.03; P = 0.006) and having a myocardial infarction (MI) (n = 156) by 50 years of age (3.17, 1.46-6.88, P = 0.007). The 121Q variant was also associated with an increased risk for CAD (1.47, 1.01-2.18; P = 0.049) in diabetic patients who did not smoke (n = 546). In conclusion, the ENPP1/PC-1 121Q variant is associated with a progressive deterioration of the IR-atherogenic phenotype; among diabetic individuals, it is also associated with earlier onset of type 2 diabetes and MI.

The +276 G/T single nucleotide polymorphism of the adiponectin gene is associated with coronary artery disease in type 2 diabetic patients.

OBJECTIVE: Two single nucleotide polymorphisms (SNPs) at the adiponectin locus (+45T>G and +276G>T) have been associated with low circulating adiponectin levels, insulin resistance, and type 2 diabetes. We investigated whether these genetic markers are determinants of coronary artery disease (CAD) in type 2 diabetic patients. RESEARCH DESIGN AND METHODS: A total of 376 consecutive type 2 diabetic patients were studied: 142 case subjects with coronary stenosis >50% or previous myocardial infarction and 234 control subjects with no symptoms, no electrocardiogram (ECG) signs of myocardial ischemia, and a normal ECG stress test (n = 189) and/or (n = 45) with coronary stenosis T polymorphism is a determinant of CAD risk in type 2 diabetic patients. This marker may assist in the identification of diabetic individuals at especially high risk of CAD, so that preventive programs can be targeted at these subjects.

An ATG repeat in the 3'-untranslated region of the human resistin gene is associated with a decreased risk of insulin resistance.

Resistin is overexpressed in human adipose tissue of obese individuals and is likely to modulate insulin sensitivity. Resistin is, therefore, a candidate gene for insulin resistance. We searched for polymorphisms in the resistin gene by single strand conformation polymorphism and direct sequencing. An ATG triplet repeat in the 3'-untranslated region was identified and considered for association with insulin resistance. Three alleles were identified (allele 1: 8 repeats, allele frequency, 0.3%; allele 2: 7 repeats; allele frequency, 94.5%; allele 3: 6 repeats; allele frequency, 5.2%). Two hundred and three unrelated white Caucasian nondiabetic subjects from Sicily and 456 from the Gargano area (center east coast of Italy) were analyzed. Among Sicilians, subjects carrying allele 3 had a lower fasting insulin and insulin resistance index (homeostasis model assessment of insulin resistance; P < 0.001 for both) and glucose (P = 0.025) and insulin (P = 0.002) levels during the oral glucose tolerance test. In subjects from Gargano, those carrying allele 3 had lower fasting plasma glucose levels and serum triglycerides (P = 0.01 for both). When the 2 populations were analyzed together, subjects carrying allele 3 had lower fasting insulin levels (P < 0.005), homeostasis model assessment of insulin resistance (P < 0.005), and serum triglycerides (P = 0.01). In conclusion, our data suggest that subjects carrying allele 3 of the resistin gene are characterized by relatively high insulin sensitivity.

Development and validation of a predicting model of all-cause mortality in patients with type 2 diabetes.

OBJECTIVE: To develop and validate a parsimonious model for predicting short-term all-cause mortality in patients with type 2 diabetes mellitus (T2DM). RESEARCH DESIGN AND METHODS: Two cohorts of patients with T2DM were investigated. The Gargano Mortality Study (GMS, n = 679 patients) was the training set and the Foggia Mortality Study (FMS, n = 936 patients) represented the validation sample. GMS and FMS cohorts were prospectively followed up for 7.40 ± 2.15 and 4.51 ± 1.69 years, respectively, and all-cause mortality was registered. A new forward variable selection within a multivariate Cox regression was implemented. Starting from the empty model, each step selected the predictor that, once included into the multivariate Cox model, yielded the maximum continuous net reclassification improvement (cNRI). The selection procedure stopped when no further statistically significant cNRI increase was detected. RESULTS: Nine variables (age, BMI, diastolic blood pressure, LDL cholesterol, triglycerides, HDL cholesterol, urine albumin-to-creatinine ratio, and antihypertensive and insulin therapy) were included in the final predictive model with a C statistic of 0.88 (95% CI 0.82-0.94) in the GMS and 0.82 (0.76-0.87) in the FMS. Finally, we used a recursive partition and amalgamation algorithm to identify patients at intermediate and high mortality risk (hazard ratio 7.0 and 24.4, respectively, as compared with those at low risk). A web-based risk calculator was also developed. CONCLUSIONS: We developed and validated a parsimonious all-cause mortality equation in T2DM, providing also a user-friendly web-based risk calculator. Our model may help prioritize the use of available resources for targeting aggressive preventive and treatment strategies in a subset of very high-risk individuals.