Complete data from hyperglycemic and hyperinsulinemic-euglycemic clamps were available for 330 youth: 73 normal weight, 168 obese with normal glucose tolerance, 57 obese with impaired glucose tolerance, and 32 obese with type 2 diabetes. The correlation between hcDI and 2cDI and Bland-Altman analysis of agreement between the two were examined.

Insulin sensitivity and first-phase insulin from hcDI showed a hyperbolic relationship. The hcDI correlated significantly with 2cDI in the groups combined (r = 0.85, P < 0.001) and within each group separately (r ≥ 62, P < 0.001). Similar to 2cDI, hcDI showed a declining pattern of β-cell function across the glucose-tolerance groups. Overall, hcDI values were 27% greater than 2cDI, due to the hyperglycemic versus euglycemic conditions, reflected in a positive bias with Bland-Altman analysis.

β-Cell function relative to insulin sensitivity could be accurately evaluated from a single hyperglycemic clamp, obviating the need for two separate clamp experiments, when lessening participant burden and reducing research costs are important considerations.

In 107 patients with diabetes, neuropathy, a recently healed plantar foot ulcer, and custom-made footwear, footwear use was measured during 7 consecutive days using a shoe-worn, temperature-based monitor. Daily step count was measured simultaneously using an ankle-worn activity monitor. Patients logged time away from home. Adherence was calculated as the percentage of steps that prescription footwear was worn. Determinants of adherence were evaluated in multivariate linear regression analysis.

Mean ± SD adherence was 71 ± 25%. Adherence at home was 61 ± 32%, over 3,959 ± 2,594 steps, and away from home 87 ± 26%, over 2,604 ± 2,507 steps. In 35 patients with low adherence (<60%), adherence at home was 28 ± 24%. Lower BMI, more severe foot deformity, and more appealing footwear were significantly associated with higher adherence.

The results show that adherence to wearing custom-made footwear is insufficient, particularly at home where patients exhibit their largest walking activity. This low adherence is a major threat for reulceration. These objective findings provide directions for improvement in adherence, which could include prescribing specific off-loading footwear for indoors, and they set a reference for future comparative research on footwear adherence in diabetes.

Data of 4,135 participants of the Rotterdam Study, a prospective population-based cohort, were available (mean follow-up 12.2 years). At baseline, 420 participants with type 2 diabetes were classified by glucose control (according to HbA_1c calculated from fructosamine), resulting in three comparison groups: adequately controlled diabetes (ACD; n = 203; HbA_1c <7.5%), inadequately controlled diabetes (ICD; n = 217; HbA_1c ≥7.5%), and no diabetes (n = 3,715). Models adjusted for sex, age, height, and weight (and femoral neck BMD) were used to test for differences in bone parameters and fracture risk (hazard ratio [HR] [95% CI]).

The ICD group had 1.1–5.6% higher BMD, 4.6–5.6% thicker cortices, and –1.2 to –1.8% narrower femoral necks than ACD and ND, respectively. Participants with ICD had 47–62% higher fracture risk than individuals without diabetes (HR 1.47 [1.12–1.92]) and ACD (1.62 [1.09–2.40]), whereas those with ACD had a risk similar to those without diabetes (0.91 [0.67–1.23]).

Poor glycemic control in type 2 diabetes is associated with fracture risk, high BMD, and thicker femoral cortices in narrower bones. We postulate that fragility in apparently "strong" bones in ICD can result from microcrack accumulation and/or cortical porosity, reflecting impaired bone repair.

We determined VEGF levels in plasma collected in both citrate and PECT, a medium that inactivates platelets, in a cross-sectional cohort of 21 healthy subjects and 64 patients with type 1 diabetes. In addition, we evaluated whether VEGF levels in both types of plasma correlated with the presence of diabetes, glycemic control, markers of in vivo or ex vivo platelet activation, and degree of diabetic retinopathy and nephropathy.

VEGF levels were invariably low in PECT plasma of both nondiabetic and diabetic subjects and were unrelated to any other diabetes-related variable studied. In contrast, VEGF levels in citrate plasma were 150% higher in diabetic patients than in control subjects and correlated with diabetes-related variables. Multiple linear regression analysis showed that levels of platelet factor 4, a marker for ex vivo platelet activation, and HbA_1c were the independent predictors of VEGF levels in citrate plasma. Platelet activation, in vivo and ex vivo, was similar in diabetic persons and control subjects.

Like serum, citrate plasma is not suitable for reliable measurements of circulating VEGF. The low levels of VEGF in vivo, as represented by measurements in PECT plasma in our study, do not support a role of circulating VEGF in endothelial dysfunction in type 1 diabetes. Higher levels of VEGF in citrate plasma samples of diabetic persons do not represent the in vivo situation, but mainly originate from higher artificial ex vivo release from platelets correlating with the degree of glycemic control.

We evaluated 82 T1D patients (26 males and 56 females, aged 31.1 ± 8.6 years, BMI 23.5 ± 3.3 kg/m², disease duration 12.8 ± 8.3 years) and 82 controls (22 females and 60 males, aged 32.9 ± 5.8 years, BMI 23.9 ± 4.8 kg/m²). Spinal and femoral BMD (as Z-score, Z-LS and Z-FN, respectively) and the prevalence of VFx were evaluated by dual X-ray absorptiometry.

T1D patients had lower Z-LS and Z-FN than controls (–0.55 ± 1.3 vs. 0.35 ± 1.0, P < 0.0001, and –0.64 ± 1.1 vs. 0.29 ± 0.9, P < 0.0001, respectively) and a higher prevalence of VFx (24.4 vs. 6.1%, P = 0.002). Age, diabetes duration, age at diabetes manifestation, glycosylated hemoglobin, Z-LS, Z-FN, and the prevalence of chronic complications were similar for patients with and without VFx. In the logistic regression analysis, the presence of VFx was associated with the presence of T1D but not with lumbar spine BMD. Whereas moderate or severe VFx was associated with low lumbar spine BMD in the whole combined group of T1D patients and controls, there was no association between moderate or severe VFx and lumbar spine BMD in the T1D group.

T1D patients have low BMD and elevated prevalence of asymptomatic VFx, which is associated with the presence of T1D independently of BMD.

For evaluation of hormonal secretion and insulin sensitivity, 10 overweight patients without type 2 diabetes (age 61 ± 19.3 years and BMI 27.9 ± 5.3 kg/m²) underwent a mixed-meal test and a hyperinsulinemic-euglycemic clamp before and after pylorus-preserving pancreatoduodenectomy for ampulloma.

All patients experienced a reduction in insulin (P = 0.002), C-peptide (P = 0.0002), and gastric inhibitory peptide (GIP) secretion (P = 0.0004), while both fasting and postprandial glucose levels increased (P = 0.0001); GLP-1 and glucagon responses to the mixed meal increased significantly after surgery (P = 0.02 and 0.031). While changes in GIP levels did not correlate with insulin, glucagon, and glucose levels, the increase in GLP-1 secretion was inversely related to the postsurgery decrease in insulin secretion (R² = 0.56; P = 0.012) but not to the increased glucagon secretion, which correlated inversely with the reduction of insulin (R² = 0.46; P = 0.03) and C-peptide (R² = 0.37; P = 0.04). Given that the remaining pancreas presumably has preserved intraislet anatomy, insulin secretory capacity, and α- and β-cell interplay, our data suggest that the increased glucagon secretion is related to decreased systemic insulin.

Pylorus-preserving pancreatoduodenectomy was associated with a decrease in GIP and a remarkable increase in GLP-1 levels, which was not translated into increased insulin secretion. Rather, the hypoinsulinemia may have caused an increase in glucagon secretion.

Japanese type 2 diabetic patients (n = 618) with serum creatinine ≤1.0 mg/dL and without overt proteinuria were enrolled between 1996 and 2000 and followed up until 2011. Baseline urinary L-FABP was measured with an enzyme-linked immunosorbent assay. The primary end points were renal and cardiovascular composites (hemodialysis, myocardial infarction, angina pectoris, stroke, cerebral hemorrhage, and peripheral vascular disease). The secondary renal outcomes were the incidence of a 50% decline in estimated glomerular filtration rate (eGFR), progression to an eGFR <30 mL/min/1.73 m², and the annual decline rate in eGFR.

During a 12-year median follow-up, 103 primary end points occurred. The incidence rate of the primary end point increased in a stepwise manner with increases in urinary L-FABP. In Cox proportional hazards analysis, the adjusted hazard ratio in patients with the highest tertile of urinary L-FBAP was 1.93 (95% CI 1.13–3.29). This relationship was observed even when analyzed separately in normoalbuminuria and microalbuminuria. Patients with the highest tertile of urinary L-FABP also demonstrated a higher incidence of the secondary renal outcomes.

Our results indicate that urinary L-FABP may be a predictive marker for renal and cardiovascular prognosis in type 2 diabetic patients without advanced nephropathy.

A prospective, monocenter, observational study was designed to follow eyes/patients with type 2 diabetes and NPDR (Early Treatment Diabetic Retinopathy Study levels 20 and 35) with no prior laser treatment for 2 years or until development of CSME. A total of 410 patients, one eye per patient, fulfilled the inclusion/exclusion criteria and were included in the study. Ophthalmologic examinations including best corrected visual acuity, fundus photography, and optical coherence tomography were performed at baseline, 6 months, and at the last study visit (24 months or before laser treatment).

A total of 348 eyes/patients performed the 24-month visit or developed CSME. Of these 348 eyes/patients, 26 developed CSME. HbA_1c levels at baseline and MA turnover (i.e., the sum of the MA formation and disappearance rates) computed during the first 6 months of follow-up were found to be independently predictive factors for development of CSME. MA turnover was 11.2 ± 11.2 in the 26 eyes/patients that developed CSME and 5.0 ± 5.2 in the remaining 322 (P < 0.001). Higher MA turnover values correlated with earlier development of CSME. MA turnover predictive values for CSME development were, for the positive predictive value, 20% and for the negative predictive value, 96%.

MA turnover calculated with the RetmarkerDR predicts development of CSME in eyes with NPDR. Low MA turnover values identify well the eyes that are less likely to develop CSME in a 2-year period.

Glycosuria was measured before and after a single ipragliflozin dose in 8 nondiabetic subjects and 57 T2DM patients (age 62 ± 9 years, fasting glucose 133 ± 39 mg/dL, mean ± SD) with normal renal function (assessed as the estimated glomerular filtration rate [eGFR]) (eGFR₁ ≥90 mL · min^–1 · 1.73 m^–2), mild (eGFR₂ ≥60 to <90), moderate (eGFR₃ ≥30 to <60), or severe reduction in eGFR (eGFR₄ ≤15 to <30).

Ipragliflozin significantly increased urinary glucose excretion in each eGFR class (P < 0.0001). However, ipragliflozin-induced glycosuria declined (median [IQR]) across eGFR class (from 46 mg/min [33] in eGFR₁ to 8 mg/min [7] in eGFR₄, P < 0.001). Ipragliflozin-induced fractional glucose excretion (excretion/filtration) was 39% [27] in the T2DM patients (pooled data), similar to that of the nondiabetic subjects (37% [17], P = ns). In bivariate analysis of the pooled data, ipragliflozin-induced glycosuria was directly related to eGFR and fasting glucose (P < 0.0001 for both, r² = 0.55), predicting a decrement in 24-h glycosuria of 15 g for each 20 mL/min decline in eGFR and an increase of 7 g for each 10 mg/dL increase in glucose above fasting normoglycemia.

In T2DM patients, ipragliflozin increases glycosuria in direct, linear proportion to GFR and degree of hyperglycemia, such that its amount can be reliably predicted in the individual patient. Although absolute glycosuria decreases with declining GFR, the efficiency of ipragliflozin action (fractional glucose excretion) is maintained in patients with severe renal impairment.

The relationship between retinopathy, its 4-year progression, and CV outcomes (CV death or nonfatal myocardial infarction or stroke) was analyzed in participants in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial who also participated in the ACCORD Eye Study. Retinopathy was classified as either none, mild, moderate, or severe, and worsening was classified as a <2-step, 2–3-step, or >3-step change (that included incident laser therapy or vitrectomy).

Participants (n = 3,433) of mean age 61 years had baseline retinal photographs (seven stereoscopic fields). Compared with no retinopathy, the adjusted HRs (95% CI) for the CV outcome rose from 1.49 (1.12–1.97) for mild retinopathy to 2.35 (1.47–3.76) for severe retinopathy. A subset of 2,856 was evaluated for progression of diabetic retinopathy at 4 years. The hazard of the primary outcome increased by 38% (1.38 [1.10–1.74]) for every category of change in retinopathy severity. Additional adjustment for the baseline and follow-up levels of A1C, systolic blood pressure, and lipids either individually or together rendered the relationships between worsening and CV outcomes nonsignificant.

Both the severity of retinopathy and its progression are determinants of incident CV outcomes. The retina may provide an anatomical index of the effect of metabolic and hemodynamic factors on future CV outcomes.

Fifty-four patients with type 2 diabetes mellitus underwent comprehensive neurologic assessment, nerve-conduction studies, and nerve-excitability assessment. Neuropathy severity was assessed using the Total Neuropathy Score. Neuropathy-specific QoL was assessed using a DN-specific QoL questionnaire (Neuropathy-Specific Quality of Life Questionnaire [NeuroQoL]). Glycosylated hemoglobin and BMI were recorded in all patients.

NeuroQoL scores indicated significant QoL impairment (mean 9.08 ± 5.93). Strength-duration time constant (SDTC), an excitability parameter reflecting sodium channel function, was strongly correlated with QoL scores (r = 0.545; P < 0.005). SDTC was prolonged in 48.6% of patients who experienced neuropathic symptoms. A significant correlation was also noted between SDTC and neuropathy severity (r = 0.29; P < 0.05). This relationship was strengthened when looking specifically at patients with clinically graded neuropathy (r = 0.366; P < 0.05).

The current study has demonstrated an association between markers of sodium channel function and QoL in DN. The study demonstrates that excitability techniques may identify patients in whom altered sodium channel function may be the dominant abnormality. The findings suggest that excitability techniques may have a role in clinical decision making regarding neuropathic treatment prescription.

In a double-blind, controlled, randomized, crossover study, 19 patients with T2DM received, on two different occasions, beverages containing either AGE-BLG or C-BLG. We measured macrovascular [brachial ultrasound of flow-mediated dilatation (FMD)] and microvascular (laser-Doppler measurements of reactive hyperemia in the hand) functions at baseline (T₀), 90 (T₉₀), and 180 (T₁₈₀) min.

Following the AGE-BLG, FMD decreased at T₉₀ by 80% from baseline and remained decreased by 42% at T₁₈₀ (P < 0.05 vs. baseline, P < 0.05 vs. C-BLG at T90). By comparison, following C-BLG, FMD decreased by 27% at T₉₀ and 51% at T₁₈₀ (P < 0.05 vs. baseline at T180). A significant decrease in nitrite (T₁₈₀) and nitrate (T₉₀ and T₁₈₀), as well as a significant increase in N-carboxymethyllisine, accompanied intake of AGE-BLG. There was no change in microvascular function caused by either beverage.

In patients with T2DM, acute oral administration of a single AGE-modified protein class significantly though transiently impaired macrovascular function in concert with decreased nitric oxide bioavailability. These AGE-related changes were independent of heat treatment.

From January 2000 to December 2002, patients with type 2 diabetes aged 25–75 years without chronic kidney disease (estimated glomerular filtration rate ≥60 mL/min/1.73 m²) were consecutively recruited (n = 1,217) and followed-up in January 2011 and May 2012. Severe hypoglycemia (SH) was defined as an event requiring the assistance of another person to actively administer glucose, hospitalization, or medical care in an emergency department. We used Cox proportional hazard regression analysis to test the association between SH episodes and potential explanatory variables.

After a median 10.4 years of follow-up, 111 (12.6%) patients experienced 140 episodes of SH, and the incidence was 1.55 per 100 patient-years. Mean age and duration of diabetes were 55.3 ± 9.8 and 9.8 ± 6.5 years, respectively. The incidence of SH events was higher in older patients (P < 0.001), in those with a longer duration of diabetes (P < 0.001), in those who used insulin (P < 0.001) and sulfonylurea (P = 0.003), and in those who had macroalbuminuria (P < 0.001) at baseline. Cox hazard regression analysis revealed that SH was associated with longer duration of diabetes and the presence of macroalbuminuria (normoalbuminuria versus macroalbuminuria: hazard ratio, 2.52; 95% CI 1.31–4.84; P = 0.006).

The development of SH was independently associated with duration of diabetes and presence of macroalbuminuria, even with normal renal function in patients with type 2 diabetes.

Renal function, blood pressure, and plasma cyclic guanosine monophosphate (cGMP) were measured in 20 men and 15 women with type 1 diabetes mellitus during clamped euglycemia and clamped hyperglycemia. Renal function, blood pressure, and plasma cGMP responses to graded infusions of intravenous l-arginine and N^G-monomethyl-l-arginine (l-NMMA) were measured during clamped hyperglycemia.

Subjects were young, normotensive, normoalbuminuric men and women who adhered to a high-sodium, moderate-protein diet. Plasma cGMP levels during euglycemia were generally lower in men compared with women, and systolic blood pressure (SBP) was higher in men. In response to hyperglycemia, cGMP levels did not change in men but did decline in women (–1.10 ± 0.20 vs. +0.05 ± 0.20 pmol/L, between-group effect of hyperglycemia on cGMP; P = 0.012). Hyperglycemia also was associated with an increase in SBP, glomerular filtration rate (GFR) (124 ± 6 to 143 ± 7 mL/min/1.73 m²; P = 0.003) and filtration fraction (FF) in women, but these parameters did not change in men. In response to l-arginine during hyperglycemia, the increase in cGMP was exaggerated in women versus men and GFR and FF decreased in women only, back toward baseline values observed during clamped euglycemia. l-NMMA infusion did not exaggerate changes in hemodynamic function in response to hyperglycemia.

 l-Arginine reversed the renal hemodynamic effects of hyperglycemia in women, suggesting that nitric oxide is an important regulator of sex-dependent vascular responses to hyperglycemia in humans.

Six healthy lean females were studied for 72 h in a cross-over interventional study under three different conditions: on isocaloric diet and in a fasting state with administration of either placebo or metreleptin in physiological replacement doses. Blood samples were obtained hourly from 8:00 a.m. on day 4 until 8:00 a.m. on day 5.

FGF-21 exhibited day–night variation pattern during the isocaloric fed state. Fasting significantly increased FGF-21 levels (P < 0.01) via a leptin-independent pathway. Day–night variation pattern in the fed state was lost on fasting. Leptin replacement in the hypoleptinemic state restored approximate entropy of FGF-21 time series but did not alter circulating levels. FGF-21 levels were closely cross-correlated with FFA levels in all three states.

A day–night variation in the levels of FGF-21 exists in young lean females in the fed state. Energy deprivation increases FGF-21 levels via a leptin-independent pathway. The interaction between FGF-21 and starvation-induced lipolysis, as indicated by its close cross-correlations with FFA in both fed state and energy deprivation, needs to be studied further.

In a prospective trial (NCT01102699), we tested BM responsiveness to 5 μg/kg human recombinant granulocyte colony–stimulating factor (hrG-CSF) in 24 individuals with DM (10 type 1 and 14 type 2) and 14 individuals without DM. Before and 24 h after hrG-CSF, we quantified circulating stem/progenitor cells and total and differential white blood cell counts. We also evaluated in vivo the proangiogenic capacity of peripheral blood mononuclear cells using the Matrigel plug assay.

In response to hrG-CSF, levels of CD34⁺ cells and other progenitor cell phenotypes increased in subjects without DM. Patients with DM had significantly impaired mobilization of CD34⁺, CD133⁺, and CD34⁺CD133⁺ hematopoietic stem cells and CD133⁺KDR⁺ endothelial progenitors, independently of potential confounders. The in vivo angiogenic capacity of peripheral blood mononuclear cells significantly increased after hrG-CSF in control subjects without DM, but not in patients with DM. DM was also associated with the inability to upregulate CD26/DPP-4 on CD34⁺ cells, which is required for the mobilizing effect of granulocyte colony–stimulating factor.

Stem and proangiogenic cell mobilization in response to hrG-CSF is impaired in DM, possibly because of maladaptive CD26/DPP-4 regulation. These alterations may hamper tissue repair and favor the development of cardiovascular complications.

Capillaroscopy was performed before and after l-arginine infusion in 48 diabetic patients (26 women and 22 men; age, 39.8 ± 6.3 years) and 24 volunteers free of any chronic disease (13 women and 11 men; age, 38.0 ± 6.7 years). The skin microcirculation reactivity, as expressed by the percentage of area covered by capillaries (coverage) and the distance between capillaries (distance), and the relationship between microcirculation reactivity and the presence of microangiopathic complications were assessed.

The distance before l-arginine infusion was significantly lower in patients than in controls (221 [153–311] vs. 240 [185–356] µm; P = 0.02) and did not differ after l-arginine infusion (223.5 [127–318] vs. 242.5 [181–341] µm; P = 0.27). The difference between the coverage values obtained before and after l-arginine infusion (coverage) was significantly different from zero in the control group but not in the diabetes group. Patients with later onset of diabetes were characterized by decreased skin microcirculation reactivity when compared with patients with earlier onset of diabetes (–1.18 [–5.07 to 11.60] vs. 1.36 [–6.00 to 8.06]; P = 0.02) despite the higher prevalence of retinopathy in patients with earlier onset of diabetes (64% vs. 26%; P = 0.02).

Skin microvascular reactivity is impaired in patients with later onset of type 1 diabetes. Capillaroscopy with l-arginine infusion is useful for the identification of skin microangiopathy in type 1 diabetes.

Using a laser Doppler velocimetry system, we obtained the retinal blood flow (RBF) values by simultaneously measuring the retinal vessel diameter and blood velocity. To determine if the RBF is affected in the presence of renal dysfunction, we also evaluated the renal function using the estimated glomerular filtration rate calculated by age and serum creatinine level.

We recruited 169 eyes of 169 consecutive Japanese patients with type 2 diabetes, no or minimal diabetic retinopathy, and normo/microalbuminuria (mean age ± SD, 59.0 ± 11.1 years). We divided the patients into four groups based on the stage of chronic kidney disease (CKD) (non-CKD, n = 99; CKD stage 1, n = 22; stage 2, n = 27; stage 3, n = 21). We found significant (P = 0.035) decreases in RBF with decreased vessel diameter (P = 0.017) but no difference in blood velocity (P = 0.54) in stage 3 CKD compared with the non-CKD group. Multiple regression analysis showed that the CKD stage was significantly (P = 0.02) and independently associated with decreased RBF.

Our results indicated that the vessel diameter and RBF in the retinal arterioles decrease in patients with type 2 diabetes with stage 3 CKD, suggesting that impaired renal function might be associated with decreased RBF, probably via constriction of the retinal arterioles, in early-phase diabetic retinopathy.

Participants were recruited consecutively from a population-based cohort: NGT (n = 39), IGT (n = 29), and T2D (n = 51). Electrophysiological measures included nerve conduction studies and thermal thresholds. Intraepidermal nerve fiber density (IENFD) in skin biopsies was calculated.

There was no difference between IGT and NGT in sural nerve conduction, IENFD, and thermal thresholds. IENFD was significantly lower in T2D (median = 2.8 fibers/mm [interquartile range 1.1–4.7 fibers/mm]) than NGT individuals (4.5 fibers/mm [3.4–6.1 fibers/mm]; P < 0.05). T2D participants had poorer nerve conduction and higher heat thresholds than NGT and IGT.

Large and small nerve function in people with IGT did not differ from those with NGT. Our finding does not support the existence of neuropathy in a prediabetic stage.

Circulating isoleucine, leucine, valine, phenylalanine, tyrosine, and six additional amino acids were quantified in 1,680 individuals from the population-based Cardiovascular Risk in Young Finns Study (baseline age 32 ± 5 years; 54% women). Insulin resistance was estimated by homeostasis model assessment (HOMA) at baseline and 6-year follow-up. Amino acid associations with HOMA of insulin resistance (HOMA-IR) and glucose were assessed using regression models adjusted for established risk factors. We further examined whether amino acid profiling could augment risk assessment of insulin resistance (defined as 6-year HOMA-IR >90th percentile) in early adulthood.

Isoleucine, leucine, valine, phenylalanine, and tyrosine were associated with HOMA-IR at baseline and for men at 6-year follow-up, while for women only leucine, valine, and phenylalanine predicted 6-year HOMA-IR (P < 0.05). None of the other amino acids were prospectively associated with HOMA-IR. The sum of branched-chain and aromatic amino acid concentrations was associated with 6-year insulin resistance for men (odds ratio 2.09 [95% CI 1.38–3.17]; P = 0.0005); however, including the amino acid score in prediction models did not improve risk discrimination.

Branched-chain and aromatic amino acids are markers of the development of insulin resistance in young, normoglycemic adults, with most pronounced associations for men. These findings suggest that the association of branched-chain and aromatic amino acids with the risk for future diabetes is at least partly mediated through insulin resistance.

The baseline values of serum and urinary cystatin C were measured as primary parameters and those of urinary nonalbumin protein (NAP) were measured as secondary parameters. In this prospective observational study, a total of 237 type 2 diabetic patients were followed up for 29 months (13–44 months).

Both the urinary cystatin C-to-creatinine ratio (CCR) and NAP-to-creatinine ratio (NAPCR) were significantly different according to the degree of albuminuria. Both markers had strongly positive correlations at baseline. After adjusting for several clinical factors, both urinary CCR and NAPCR had significant associations with the decline of the estimated glomerular filtration rate (eGFR) (r = 0.160, P = 0.021; r = 0.412, P < 0.001, respectively). Urinary CCR had positive correlations with the decline of eGFR in the subpopulation of patients with eGFR ≥60 mL/min/1.73 m². In patients with eGFR ≥60 mL/min/1.73 m² and normoalbuminuria, only urinary NAPCR showed a significant association with the decline of eGFR; urinary CCR did not. In multivariate regression analysis, the number of patients who progressed to chronic kidney disease stage 3 or greater was higher in those in the upper tertiles of both the urinary levels of cystatin C and NAP than in those in the lower tertiles.

The results of this study suggest that urinary cystatin C and NAP may be predictors of the progression of type 2 diabetic nephropathy.

Twenty-six patients with DM and gastrointestinal symptoms and 23 healthy control subjects were studied in a 3T scanner. The apparent diffusion coefficient (i.e., diffusivity of water) and fractional anisotropy (FA) (i.e., organization of fibers) were assessed in the "sensory matrix" (cingulate cortex, insula, prefrontal and secondary sensory cortex, amygdala, and corona radiata) and in corpus callosum.

Patients had decreased FA values compared with control subjects in 1) all areas (P = 0.025); 2) anterior (P < 0.001), mid- (P = 0.001), and posterior (P < 0.001) cingulate cortex; 3) prefrontal cortex gray matter (P < 0.001); 4) corona radiata (P < 0.001); 5) secondary sensory cortex (P = 0.008); and 6) anterior white matter (P = 0.045), anterior gray matter (P = 0.002), and posterior gray matter (P = 0.002) insula. No difference was found in corpus callosum (P > 0.05). The microstructural changes in some areas correlated with clinical parameters such as bloating (anterior insula), mental well-being (anterior insula, prefrontal cortex, and mid-cingulated and corona radiata), autonomic function based on electrocardiographic results (posterior insula and anterior cingulate), and presence of gastroparesis (anterior insula).

The findings of this explorative study indicate that microstructural changes of brain areas involved in visceral sensory processing are associated with autonomic dysfunction and therefore may be involved in the pathogenesis of gastrointestinal symptoms in DM patients.

We used data from the 970 patients who attended the screening for diabetes complications 6 years after the diagnosis. Cox proportional hazards regression was used to examine the relationship between urinary markers of DNA oxidation (8-oxo-7,8-dihydro-2'-deoxyguanosine [8-oxodG] [n = 938]) and RNA oxidation (8-oxoGuo [n = 936]) and mortality.

During a median of 9.8 years of follow-up, 654 patients died. Urinary 8-oxoGuo assessed 6 years after the diagnosis was significantly associated with mortality. The multivariate-adjusted hazard ratios for all-cause and diabetes-related mortality of patients with 8-oxoGuo levels in the highest quartile compared with those in the lowest quartile were 1.86 (95% CI 1.34–2.58) and 1.72 (1.11–2.66), respectively. Conversely, 8-oxodG was not associated with mortality. In addition, we found an association between changes in 8-oxoGuo from diagnosis to 6-year follow-up and mortality, with increased risk in patients with an increase and decreased risk in patients with a decrease in 8-oxoGuo.

The RNA oxidation marker 8-oxoGuo is an independent predictor of mortality in patients with established and treated type 2 diabetes, and changes in 8-oxoGuo during the first 6 years after diagnosis are associated with mortality.

MRI measures were obtained on 308 elders (mean age 83.3 years; n = 85 with diabetes) from the Health ABC Healthy Brain Substudy. We performed a series of linear regressions and used standardized β values to estimate the cross-sectional association between diabetes and macrostructural (gray matter volume [GMV] and white matter hyperintensities [WMHs]) and microstructural (mean diffusivity [MD] and fractional anisotropy [FA]) measures for the total brain and ROIs. Models were adjusted for age, race, and sex; GMV values for ROIs were also adjusted for total brain volume (TBV).

In multivariate-adjusted models, diabetes was associated with lower total GMV (P = 0.0006), GMV in the putamen (P = 0.02 for left and right), and TBV (P = 0.04) and greater cerebral atrophy (P = 0.02). There was no association with WMHs. On microstructural measures, diabetes was associated with reduced FA for total white matter (P = 0.006) and greater MD for the hippocampus (P = 0.006 left; P = 0.01 right), dorsolateral prefrontal cortex (P = 0.0007, left; P = 0.002, right), left posterior cingulate (P = 0.02), and right putamen (P = 0.02). Further adjustment for stroke, hypertension, and myocardial infarction produced similar results.

In this cross-sectional study, elders with diabetes compared with those without had greater brain atrophy and early signs of neurodegeneration. Further studies are needed to determine whether these structural changes associated with diabetes predict risk of cognitive decline.