Novel Hypothesis to Explain Why SGLT2 Inhibitors Inhibit Only 30–50% of Filtered Glucose Load in Humans

Inhibitors of sodium-glucose cotransporter 2 (SGLT2) are a novel class of antidiabetes drugs, and members of this class are under various stages of clinical development for the management of type 2 diabetes mellitus (T2DM). It is widely accepted that SGLT2 is responsible for >80% of the reabsorption of the renal filtered glucose load. However, maximal doses of SGLT2 inhibitors fail to inhibit >50% of the filtered glucose load. Because the clinical efficacy of this group of drugs is entirely dependent on the amount of glucosuria produced, it is important to understand why SGLT2 inhibitors inhibit <50% of the filtered glucose load. In this Perspective, we provide a novel hypothesis that explains this apparent puzzle and discuss some of the clinical implications inherent in this hypothesis.Despite the irrefutable evidence for the important role of hyperglycemia in the development of diabetic microvascular complications (1,2) and the large number of antidiabetes agents available for the management of individuals with type 2 diabetes mellitus (T2DM), the majority of subjects with T2DM still manifest suboptimal glycemic control (3). Over half of all patients with T2DM in the U.S. fail to meet the American Diabetes Association treatment goal of HbA_1c <7%, and a smaller number of subjects achieve the American College of Clinical Endocrinologists goal of HbA_1c <6.5% with existing therapies (3). Progressive β-cell failure, weight gain, and hypoglycemia are some of the obstacles for the achievement of optimal glycemic control (HbA_1c ≤6.5) in patients with T2DM. Therefore, additional antidiabetes agents that are effective in lowering the plasma glucose concentration without weight gain and hypoglycemia are required for the treatment of T2DM individuals. Sodium-glucose cotransporter 2 (SGLT2) inhibitors represent a novel class of antihyperglycemic drugs that inhibit glucose reuptake in the kidney and are under clinical development for the treatment of T2DM (4). Dapagliflozin is approved in Europe, and canagliflozin recently was approved in the U.S. This class of drugs lowers the plasma glucose concentration by inhibiting SGLT2, leading to glucosuria. Because SGLT2 inhibitors produce urinary glucose loss, they also promote weight loss. Since the mechanism of action of the SGLT2 inhibitors is independent of insulin action and insulin secretion, they lower the plasma glucose concentration without increasing the risk of hypoglycemia. Moreover, because of this unique mechanism of action, SGLT2 inhibitors are effective in lowering the HbA_1c at all stages of diabetes (5), and they can be used in combination with all other antihyperglycemic agents including insulin (6).The efficacy of SGLT2 inhibitors to reduce the HbA_1c and promote weight loss is highly dependent upon the amount of glucosuria produced by these agents. Clinical studies have demonstrated that the glucosuria produced by these agents is less than would be expected from the inhibition of SGLT2. In this Perspective, we suggest an explanation for this paradox, discuss some of the clinical implications of this explanation, and suggest mechanisms to improve the clinical efficacy of SGLT2 inhibitors.     

Elevated glycosylated haemoglobin (HbA1c) is a risk marker in coronary artery bypass surgery

Objective. To evaluate if glycosylated haemoglobin 1 (HbA_1c) was associated with increased risk of infection and mortality after coronary artery bypass grafting (CABG). Design. Prospective observational study. Preoperative HbA_1c concentrations were correlated to outcome in patients followed for an average of 3.5 years after CABG. Results. HbA_1c was ≥6% in 68% of 161 patients with diabetes mellitus (DM) and in 3% of 444 patients without DM. Superficial sternal wound infection was observed in 13.9% if HbA_1c ≥6% versus in 5.5% if <6% (p=0.007). Mediastinitis occurred in 4.9% if HbA_1c≥6% and in 2.1% if HbA_1c<6% (p=0.20) (Hazard ratio (HR) 1.9, 95% CI 0.6-5.9). Follow-up mortality was 18.9% in patients with HbA_1c≥6% compared to 4.1% if HbA_1c<6% (p<0.001) with HR 5.4, (95% CI 3.0-10.0) after multivariable adjustment. The risk of death was similar regardless of DM diagnosis. Conclusions. HbA_1c ≥6% was associated with an increased risk of postoperative superficial sternal wound infections and a trend for higher mediastinitis rate and significantly higher mortality three years after CABG.     

Transtubular potassium concentration gradient: a useful test to estimate renal aldosterone bio-activity in infants and children

The present investigation was designed to validate the usefulness of transtubular potassium (K) concentration gradient (TTKG) as an indicator of aldosterone bio-activity in infants and children. TTKG was calculated by the formula: [K]urine: (urine/plasma)osmolality/[K]venous blood. We compared this index with fractional K excretion (FEK) and urine K concentration to urine sodium (Na) concentration ratio (UK/UNa) in 473 normal children aged 1 month-15 years. Values of TTKG followed a non-gaussian distribution (median, 6.3; 3rd centile, 4.1; 97th centile, 13.4). TTKG in infants (n = 108; median, 7.8) was significantly higher than in children (n = 365; median, 6.0). TTKG correlated directly with FEK and UK/UNa. Indices of K excretion were also assessed in 13 patients with hypo- and pseudohypoaldosteronism. TTKG values varied between 1.6 and 4.1 and were all below the 3rd percentile established for the age of the subject. We conclude that calculation of TTKG is an easy and sensitive method for the evaluation of mineralocorticoid action in distal and collecting tubules.     

Improved Glycemic Control and Risk of ESRD in Patients with Type 1 Diabetes and Proteinuria

Most patients with type 1 diabetes (T1D) and proteinuria have poor glycemic control and a high risk of ESRD. We investigated whether long-term improvement of glycemic control reduces risk of ESRD in a prospective 7- to 15-year follow-up observation of 349 patients with CKD stages 1–3 enrolled in the Joslin Proteinuria Cohort of adults with T1D. All patients developed proteinuria between 1990 and 2004 and were followed until 2011 to ascertain onset of ESRD and deaths unrelated to ESRD. Furthermore, we analyzed data from 279 patients with ≥3 years of clinic follow-up available to assess the level of glycemic control after enrollment. Average HbA_1c during the 5 years before study enrollment (prebaseline) was compared with HbA_1c (postbaseline) averaged during the first half of follow-up (median, 5.1 years). Median prebaseline HbA_1c was 9.3%, decreasing to 8.7% postbaseline. Cumulative risk of ESRD after 15 years was significantly lower for patients whose HbA_1c decreased than for those whose HbA_1c increased or remained poor (29% versus 42%; P<0.001). The difference between these groups was not visible at 5 years of follow-up but became visible at 10 and 15 years of follow-up. In multivariate Cox regression analysis of ESRD risk, the hazard ratio corresponding to a 1–percentage point improvement in postbaseline HbA_1c was 0.76 (95% confidence interval, 0.63 to 0.91; P=0.003). In conclusion, results of this study suggest that long-term sustained improvement in HbA_1c decelerates eGFR loss and delays the onset of ESRD in patients with T1D and proteinuria.     

The relationship between glycosylated hemoglobin and perioperative glucose control in patients with diabetes

Purpose

Hyperglycemia and elevated glycosylated hemoglobin (HbA_1c) are associated with perioperative morbidity in patients with diabetes, but the relationship between long-term glycemic control and perioperative glucose control is unknown. The purpose of this study was to determine the relationship between glycosylated hemoglobin (HbA_1c) and perioperative glucose in fasting patients with type 2 diabetes undergoing elective non-cardiac surgery.

Methods

This was a prospective observational study of 244 adult patients with type 2 diabetes who were evaluated before elective non-cardiac surgery at a preoperative medicine clinic in a tertiary care medical centre during the period September 2004 to May 2005. Preoperative HbA_1c levels were determined, and preoperative and postoperative glucose values were measured on the day of surgery. The primary outcome variables were preoperative and postoperative blood glucose values.

Results

Half of all study patients had an HbA_1c ≥ 7%, including 23% of patients with HbA_1c ≥ 8%. HbA_1c levels predict preoperative glucose levels, and preoperative glucose levels and duration of surgery predict postoperative glucose levels. Glucose levels in one-third of the patients with type 2 diabetes decreased during surgery without administration of insulin or glucose-regulating medications.

Conclusion

HbA_1c values may serve as biomarkers for glucose control during the immediate perioperative period in patients with type 2 diabetes undergoing elective surgery.     

Does Genetic Ancestry Explain Higher Values of Glycated Hemoglobin in African Americans?

OBJECTIVE

Glycated hemoglobin (HbA_1c) values are higher in African Americans than whites, raising the question of whether classification of diabetes status by HbA_1c should differ for African Americans. We investigated the relative contribution of genetic ancestry and nongenetic factors to HbA_1c values and the effect of genetic ancestry on diabetes classification by HbA_1c in African Americans.

RESEARCH DESIGN AND METHODS

We performed a cross-sectional analysis of data from the community-based Atherosclerosis Risk in Communities (ARIC) Study. We estimated percentage of European genetic ancestry (PEA) for each of the 2,294 African Americans without known diabetes using 1,350 ancestry-informative markers. HbA_1c was measured from whole-blood samples and categorized using American Diabetes Association diagnostic cut points (<5.7, 5.7–6.4, and ≥6.5%).

RESULTS

PEA was inversely correlated with HbA_1c (adjusted r = −0.07; P < 0.001) but explained <1% of its variance. Age and socioeconomic and metabolic factors, including fasting glucose, explained 13.8% of HbA_1c variability. Eleven percent of participants were classified as having diabetes; adjustment for fasting glucose decreased this to 4.4%. Additional adjustment for PEA did not significantly reclassify diabetes status (net reclassification index = 0.034; P = 0.94) nor did further adjustment for demographic, socioeconomic, and metabolic risk factors.

CONCLUSIONS

The relative contribution of demographic and metabolic factors far outweighs the contribution of genetic ancestry to HbA_1c values in African Americans. Moreover, the impact of adjusting for genetic ancestry when classifying diabetes by HbA_1c is minimal after taking into account fasting glucose levels, thus supporting the use of currently recommended HbA_1c categories for diagnosis of diabetes in African Americans.Glycated hemoglobin (HbA_1c) values are significantly higher in African Americans compared with whites even after adjustment for fasting blood glucose (1–4). Whether this racial difference in HbA_1c reflects true differences in hyperglycemia or differences in biologic determinants of HbA_1c unrelated to hyperglycemia is controversial (5–7), especially in the context of the American Diabetes Association recommendation to use HbA_1c ≥6.5% for diagnosis of diabetes (8).Self-reported African American race is associated with many socioeconomic factors that influence health (9), particularly diabetes risk (10). Genetically derived ancestry can be used to partially deconstruct race as it places each individual on a continuous spectrum of race as opposed to grouping all individuals into one racial group. Therefore, our main objective was to determine the contribution of genetic ancestry to HbA_1c in self-reported African Americans. Genetic ancestry may be associated with HbA_1c through direct biological effects unrelated to hyperglycemia or indirectly through social and demographic determinants of hyperglycemia (11,12). Because epidemiologic studies report higher HbA_1c values in African Americans compared with whites independent of their fasting glucose (1–4), we examine the ancestral genetic contribution to HbA_1c after accounting for fasting glucose levels. We hypothesized that 1) percentage of European ancestry (PEA) explains only a small proportion of the variability in HbA_1c in African Americans; 2) PEA and HbA_1c are associated with similar social and biologic factors; and 3) PEA does not significantly alter diabetes classification by HbA_1c independent of fasting glucose levels.     

Effects of genetic susceptibility for type 2 diabetes on the evolution of glucose homeostasis traits before and after diabetes diagnosis: data from the D.E.S.I.R. Study

OBJECTIVE

To assess the impact of genetic susceptibility on evolution toward type 2 diabetes (T2D) by analyzing time trajectories of fasting glucose, glycated hemoglobin (HbA_1c), insulin sensitivity (homeostasis model assessment [HOMA2%S]), and β-cell secretion (HOMA2%B) in a large nondiabetic cohort. We also examined whether baseline HbA_1c modified the effect of genetic predisposition on the time trajectories.

RESEARCH DESIGN AND METHODS

Time trajectories were drawn in 4,744 participants from the French Data from an Epidemiological Study on the Insulin Resistance Syndrome (D.E.S.I.R.) cohort based on samples collected every 3 years over a 9-year follow-up. Trajectories were analyzed according to the TCF7L2 common variant, a family history of T2D, and a combination of at-risk alleles from nine T2D-associated genes.

RESULTS

There was a marked decrease in HOMA2%B in parallel to a steep increase in HbA_1c over the 3 years before incident diabetes, which was not influenced by genetic predisposition when considered alone. However, after the onset of T2D, the TCF7L2 at-risk variant was associated with a greater decrease in HOMA2%B. There was a joint effect of a family history of T2D with the presence of the TCF7L2 risk allele with a greater rise in HbA_1c conferred by the coexistence of a family history and the T risk allele. An HbA_1c ≥5.7% at baseline was associated with a greater increase in both glycemia and HbA_1c levels in the presence of a combination of diabetes at-risk alleles.

CONCLUSIONS

After incident T2D, TCF7L2 at-risk variants were associated with a faster decrease in β-cell function compared with those with the CC genotype. There was a joint effect of family history of T2D and TCF7L2 risk variant on the rise in glycemia and the decrease in insulin secretion at the end of follow-up, suggesting the joint influence of the combination of diabetes genetic predisposition with familial factors on the evolution of glycemia over time.Impaired fasting glucose and type 2 diabetes (T2D) arise from a failure of the β-cell to adequately compensate for insulin resistance (1–6). Previous evidence suggests that the combination of moderately elevated glycemia, increased BMI, and family history of T2D is a strong predictor of T2D in the general population (7). After a compensatory period with a slow linear increase in fasting glucose, a transient unstable period over 2 to 3 years leads to rapidly emerging hyperglycemia and overt diabetes (8). Concomitant acceleration in both β-cell dysfunction and decreasing insulin sensitivity has recently been shown to occur before the onset of T2D (9).Previous evidence shows that genetic susceptibility for T2D could induce an early β-cell dysfunction (10–13). However, the impact of genetic predisposition to T2D on the evolution of glucose homeostasis traits over time in the years preceding T2D onset, and after T2D onset, has not been studied in a general population.The main aim of our study was to assess the impact of genetic susceptibility on evolution toward diabetes and in the years thereafter by analyzing time trajectories of fasting glucose, glycated hemoglobin (HbA_1c), β-cell function (using homeostasis model assessment [HOMA]; HOMA2%B), and insulin sensitivity (HOMA2%S) in a large population without T2D at baseline. Because the TCF7L2 polymorphism has the largest effect on T2D susceptibility among the predisposing genes discovered to date (14,15), we first analyzed the impact of the TCF7L2 polymorphism alone on trajectories and then investigated the joint effect of the TCF7L2 risk allele and a family history of T2D on the evolution of time trajectories for both HbA_1c and insulin secretion. Second, we assessed the effect of a genetic score integrating the number of at-risk alleles from nine well-defined T2D-associated variants (TCF7L2 rs7903146, CDKN2A/2B rs10811661, CDKAL1 rs7754840, PPARG rs1801282, HHEX rs1111875, IGF2BP2 rs4402960, KCNJ11 rs5219, SLC30A8 rs13266634, and WFS1 rs10010131) (15).Finally, because recent evidence shows that glycemia influences the effects of T2D-risk genes on insulin secretion (16), we assessed whether baseline HbA_1c modified the impact of diabetes at-risk genes on the evolution of fasting glucose, HbA_1c, HOMA2%B, and HOMA2%S over the follow-up in the entire cohort.     

Impact of C-Peptide Preservation on Metabolic and Clinical Outcomes in the Diabetes Control and Complications Trial

The Diabetes Control and Complications Trial established that a stimulated C-peptide concentration ≥0.2 nmol/L at study entry among subjects with up to a 5-year diabetes duration is associated with favorable metabolic and clinical outcomes over the subsequent 7 years of follow-up. Herein we further examine the association of both fasting and stimulated C-peptide numerical values with outcomes. In the intensive treatment group, for a 50% higher stimulated C-peptide on entry, such as from 0.10 to 0.15 nmol/L, HbA_1c decreased by 0.07% (0.8 mmol/mol; P = 0.0003), insulin dose decreased by 0.0276 units/kg/day (P < 0.0001), hypoglycemia risk decreased by 8.2% (P < 0.0001), and the risk of sustained retinopathy was reduced by 25% (P = 0.0010), all in unadjusted analyses. Other than HbA_1c, these effects remained significant after adjusting for the HbA_1c on entry. While C-peptide was not significantly associated with the incidence of nephropathy, it was strongly associated with the albumin excretion rate. The fasting C-peptide had weaker associations with outcomes. As C-peptide decreased to nonmeasurable concentrations, the outcomes changed in a nearly linear manner, with no threshold or breakpoint. While preservation of stimulated C-peptide at ≥0.2 nmol/L has clinically beneficial outcomes, so also does an increase in the concentration of C-peptide across the range of values.     

Evaluating the Role of Epigenetic Histone Modifications in the Metabolic Memory of Type 1 Diabetes

We assessed whether epigenetic histone posttranslational modifications are associated with the prolonged beneficial effects (metabolic memory) of intensive versus conventional therapy during the Diabetes Control and Complications Trial (DCCT) on the progression of microvascular outcomes in the long-term Epidemiology of Diabetes Interventions and Complications (EDIC) study. We performed chromatin immunoprecipitation linked to promoter tiling arrays to profile H3 lysine-9 acetylation (H3K9Ac), H3 lysine-4 trimethylation (H3K4Me3), and H3K9Me2 in blood monocytes and lymphocytes obtained from 30 DCCT conventional treatment group subjects (case subjects: mean DCCT HbA_1c level >9.1% [76 mmol/mol] and progression of retinopathy or nephropathy by EDIC year 10 of follow-up) versus 30 DCCT intensive treatment subjects (control subjects: mean DCCT HbA_1c level <7.3% [56 mmol/mol] and without progression of retinopathy or nephropathy). Monocytes from case subjects had statistically greater numbers of promoter regions with enrichment in H3K9Ac (active chromatin mark) compared with control subjects (P = 0.0096). Among the patients in the two groups combined, monocyte H3K9Ac was significantly associated with the mean HbA_1c level during the DCCT and EDIC (each P < 2.2E-16). Of note, the top 38 case hyperacetylated promoters (P < 0.05) included >15 genes related to the nuclear factor-κB inflammatory pathway and were enriched in genes related to diabetes complications. These results suggest an association between HbA_1c level and H3K9Ac, and a possible epigenetic explanation for metabolic memory in humans.     

Relevance of beta-cell function for improved glycemic control after gastric bypass surgery

BackgroundResidual beta-cell function and gastrointestinal hormones have been suggested as relevant determinants of improved glycemic control ensuing Roux-en-Y gastric bypass (RYGB). The objective of this study was to compare the glycemic control up to 24 months after RYGB in C-peptide negative morbidly obese (MO) type 1 diabetes mellitus (T1 DM) women (n = 7) and C-peptide positive (>.6 ng/mL) MO women with type 2 diabetes mellitus (T2 DM, n = 7) on basal-bolus insulin therapy. The glucagon-like peptide 1 (GLP-1) and glucagon response to a mixed meal challenge were also compared between groups.MethodsPercent excess weight loss (%EWL), HbA_1c, and daily insulin dose (DID) after RYGB were compared between groups. The GLP-1 and glucagon response (area under the curve 0–120 minutes) after a mixed meal at last follow-up visit were also compared.ResultsAt 24-months, marked %EWL was observed in women with T1 DM and women with T2 DM (mean±standard error, 82.6%±11.3% and 87.4%±30.5%, respectively; P = .722]. In women with T1 DM, HbA_1c (4 months, P<.05) and DID improved transiently (P<.05, up to 8 months) but were comparable to baseline thereafter (HbA_1c: baseline, 8.3±1.2 and 24 months, 8.2±.9, P = 1.00; DID: baseline, .61±.17 and 24 months .62±.12 IU/kg/d, P = 1.00]. In contrast, in MO women with T2 DM, HbA_1c decreased significantly throughout follow–up, with 2 patients presenting diabetes remission and all but one an HbA_1c<7% at 24 months. The GLP-1 response was comparable between groups (P = .612), and was not accompanied by suppression of the glucagon response to meal intake.ConclusionsIn the absence of residual beta-cell, RYGB results in no significant benefit on glycemic control, despite a marked response of GLP-1 to meal intake.     

Changes in HbA1c levels and body mass index after successful decompression surgery in patients with type 2 diabetes mellitus and lumbar spinal stenosis: results of a 2-year follow-up study

Background Context

Lumbar spinal stenosis (LSS) can hinder a patient's physical activity, which in turn can impair glucose tolerance and body weight regulation in patients with type 2 diabetes mellitus (DM-2). Therefore, successful lumbar surgery could facilitate glycemic control and body weight regulation.

Effect of conversion from twice-daily to once-daily tacrolimus on glucose intolerance in stable kidney transplant recipients

Background

Tacrolimus is an established immunosuppressant for the prevention and treatment of allograft rejection in organ transplantation. However, tacrolimus therapy also has several adverse effects. The main aim of this study was to evaluate the effect of conversion from twice-daily tacrolimus (tacrolimus-BID) to once-daily tacrolimus (tacrolimus-OD) on glucose intolerance in stable kidney transplant patients.

Methods

The study comprised 43 kidney transplant recipients with stable renal function. The same 1 mg:1 mg dose conversion was used for all patients. Follow-up, which included clinical evaluation and laboratory testing, was performed at 30, 60, and 120 days after conversion. The parameters for which the baseline and end-point values were determined included homeostasis model assessment of beta-cell function (HOMA-B) scores, hemoglobin A_1c (HbA_1c) levels, serum insulin levels, and fasting glucose levels.

Results

The tacrolimus trough levels did not differ significantly at 120 days after conversion. There was a significant increase in serum insulin level at 120 days after conversion (baseline, 5.6 ± 2.7 μU/mL; end point, 6.6 ± 3.4 μU/mL; P < .009). The HOMA-B score slightly increased (baseline, 58.7 ± 33.1; end point, 65.6 ± 32.8; P = .091) at 120 days after conversion, indicating beta-cell function. Serum creatinine concentration, blood glucose level, and HbA_1c level did not change significantly during follow-up examinations. Episodes of acute rejection or graft loss did not occur.

Conclusion

The results of this study suggests that conversion from tacrolimus-BID to tacrolimus-OD may benefit kidney transplant patients with glucose intolerance because of improved insulin secretion. Further studies involving a larger sample population and longer follow-up time are required to verify the results of this study.     

High hemoglobin A1c associated with increased adverse limb events in peripheral arterial disease patients undergoing revascularization

Objective

Diabetes and peripheral arterial disease (PAD) are independently associated with increased risk of amputation. However, the effect of poor glycemic control on adverse limb events has not been studied. We examined the effects of poor glycemic control (high hemoglobin A_1c level) on the risk of amputation and modified major adverse limb events (mMALEs) after lower extremity revascularization.

Adherence to clinical care guidelines for cystic fibrosis-related diabetes in 659 German/Austrian patients

BackgroundIn Germany/Austria, data on medical care for cystic fibrosis-related diabetes (CFRD) is limited.MethodsAnonymized data from 659 CFRD patients were analyzed and compared to the latest ADA/CFF guidelines.ResultsSpecialized diabetes clinics were attended less frequently than recommended (3.1 vs. 4.0 times yearly). 7.9% of patients had a complete profile of examinations: diabetes education (44.9%), HbA_1c (88.8%), blood pressure (79.5%), BMI (86.5%), lipid status (37.5%), retinopathy (29.9%), microalbuminuria (33.2%), and self-monitoring of blood glucose (71.6%). HbA_1c and blood pressure were measured less frequently than recommended (2.3 and 2.0 vs. 4.0 times yearly). Overall, guidelines were followed more frequently in children than adults. Contrary to recommendations, not all patients were treated with insulin (77.2 vs. 100.0%). Insulin therapy was initiated earlier in children than adults, but there was still a substantial delay (0.9 vs. 2.7 years after diagnosis, p < 0.001).ConclusionIn CFRD patients studied, adherence to care guidelines was suboptimal.     

Bone Modeling Indexes at Onset and During the First Year of Follow-Up in Insulin-Dependent Diabetic Children

Osteopenia has been described as a complication of insulin-dependent diabetes mellitus (IDDM). We measured bone modeling indexes during the first year of IDDM. At each time point the values obtained from diabetic children have been compared with those of control subjects. We selected 27 prepubertal children with IDDM (6.35 ± 2.16 years). We also enrolled 30 healthy prepubertal children of comparable age (5.85 ± 3.05 years). Height, height standard deviation scores, glycated haemoglobin (HbA_1C), basal c-peptide concentrations, insulin dose, serum concentrations of procollagen type I C-terminal propeptide (PICP), and collagen type I C-terminal telopeptide (ICTP) were measured at onset of IDDM and at 3, 6 and 12 months. ICTP was in the normal range at onset of IDDM and decreased during the follow-up to reach a significant difference compared to controls after 3, 6 and 12 months of insulin treatment (P < 0.04). PICP concentrations increased significantly at 3 months (P= 0.05) compared to onset. At 3 and 12 months PICP values were significantly higher than those of control children (P= 0.04). Correlations were found between PICP concentrations and HbA_1C and c-peptide at onset of diabetes (r =−0.45 and r = 0.47, respectively). Bone formation at onset of IDDM is not impaired; the introduction of insulin therapy, together with the achievement of a good metabolic control, determines an increase of bone matrix formation coupled with a decrease of bone resorption, that determines a positive balance of bone modeling. Received: 7 May 1996 / Accepted: 18 October 1996     

Targeting CXCR1/2 in the first multicenter,double-blinded,randomized trial in autologous islet transplant recipients

Several cytokines and chemokines are elevated after islet infusion in patients undergoing total pancreatectomy with islet autotransplantation (TPIAT), including CXCL8 (also known as interleukin-8), leading to islet loss. We investigated whether use of reparixin for blockade of the CXCL8 pathway would improve islet engraftment and insulin independence after TPIAT. Adults without diabetes scheduled for TPIAT at nine academic centers were randomized to a continuous infusion of reparixin or placebo (double-blinded) for 7 days in the peri-transplant period. Efficacy measures included insulin independence (primary), insulin dose, hemoglobin A_1c (HbA_1c), and mixed meal tolerance testing. The intent-to-treat population included 102 participants (age 39.5 ± 12.2 years, 69% female), n = 50 reparixin-treated, n = 52 placebo-treated. The proportion insulin-independent at Day 365 was similar in reparixin and placebo: 20% vs. 21% (p = .542). Twenty-seven of 42 (64.3%) in the reparixin group and 28/45 (62.2%) in the placebo group maintained HbA_1c ≤6.5% (p = .842, Day 365). Area under the curve C-peptide from mixed meal testing was similar between groups, as were adverse events. In conclusion, reparixin infusion did not improve diabetes outcomes. CXCL8 inhibition alone may be insufficient to prevent islet damage from innate inflammation in islet autotransplantation. This first multicenter clinical trial in TPIAT highlights the potential for future multicenter collaborations.     

Quantitative Ultrasound Measurements in Children and Adolescents with: Type 1 Diabetes

The aim of the current study was to evaluate bone status at the radius and phalanx in children and adolescents with type 1 diabetes by using quantitative ultrasound (QUS) measurements. Thirty pediatric patients, 16 male and 14 female, with type 1 diabetes of duration of 5 to 177 months and mean (± SD) age 11.3 ± 4.6 years were studied. QUS measurements were carried out using the Sunlight Omnisense 7000 S device. Speed of sound (SOS) was measured at the radius and tibia. Diabetic control was assessed by glycosylated hemoglobin (HbA_1c) measurements. Male and female patients with type 1 diabetes did not have significantly different SOS or HbA_1c values. SOS Z-scores at both the radius and tibia were negatively associated with duration of disease (r = –0 41 and r = –0.37 for the radius and tibia respectively, P < 0.05 for both correlations). Seven of 15 patients with duration of disease of >6 years had diminished SOS, defined as Z-score of <–1, at either the radius or tibia. SOS measurements at the radius showed moderate correlation with SOS at the tibia (r = 0.58, P < 0.00 l). There was no correlation between SOS and HbA_1c. In conclusion, SOS Z-scores at both the radius and tibia show a significant negative correlation with duration of insulin-dependent diabetes in children. No relation was found between SOS and metabolic control of young diabetic patients.     

Factors related to renal haemodynamics in young type-1 diabetes mellitus patients

The influence of metabolic control (HbA_1c), noradrenaline (NA) and insulin-like growth factors (IGF-I and IGF-II) on renal function and size was investigated in 11 insulin-dependent diabetes mellitus patients aged 11–17 years. Renal function was evaluated in terms of glomerular filtration rate (GFR) and effective renal plasma flow (ERPF). Renal size was determined as renal parenchymal volume (RPV) by ultrasonography. The patients' HbA_1c values ranged from 8.2% to 12.9% (normal range 5.5–8.5%) and their GFR and ERPF were higher than normal. Their IGF-II values were higher, and NA and IGF-I levels were lower than those of healthy controls. Inverse correlations between NA and GFR (r=–0.66) and NA and ERPF (r=–0.63) were found. No correlation was found between serum IGF-I and renal functional parameters. The IGF-II values correlated with GFR and HbA_1c (r=0.63,r=0.70 respectively). There were linear correlations between RPV and GFR, RPV and ERPF, HbA_1c and GFR, and ERPF and RPV. Decreased NA concentrations and increased IGF-II values appear to be factors contributing to renal hyperfunction in these patients.     

Combination of Obesity with Hyperglycemia is a Risk Factor for the Presence of Vertebral Fractures in Type 2 Diabetic Men

Although patients with type 2 diabetes show no bone mineral density (BMD) reduction, fracture risks are known to increase. It is unclear why the patients have an increased risk of fracture despite sufficient BMD. We investigated the relationships of body mass index (BMI), HbA_1c, and urinary C-peptide (uC-peptide) versus BMD, bone metabolic markers, serum adiponectin, and prevalent vertebral fracture (VF). A total of 163 Japanese type 2 diabetic men were consecutively recruited, and radiographic and biochemical data were collected. BMI was positively correlated with BMD at the whole body, lumbar spine, and femoral neck (P < 0.05) and negatively correlated with osteocalcin and urinary N-terminal cross-linked telopeptide of type-I collagen (uNTX) (P < 0.01). HbA_1c was negatively correlated with osteocalcin (P < 0.01) but not BMD at any site. Subjects were classified into four groups based on BMI and HbA_1c (group LL BMI < 24 and HbA_1c < 9, group LH BMI < 24 and HbA_1c ≧ 9, group HL BMI ≧ 24 and HbA_1c < 9, group HH BMI ≧ 24 and HbA_1c ≧ 9). Serum adiponectin, osteocalcin, and uNTX were lower and the incidence of VF was higher despite sufficient BMD in the HH group. Multivariate logistic regression analysis adjusted for age, duration of diabetes, uC-peptide, and estimated glomerular filtration rate showed that the HH group was associated with the presence of a VF and multiple VFs (odds ratio [OR] = 3.056, 95% confidence interval [CI] 1.031–9.056, P = 0.0439, and OR = 5.415, 95% CI 1.126–26.040, P = 0.0350, respectively). Combination of obesity with hyperglycemia was a risk factor for VF despite sufficient BMD in diabetic men.     

Non-albuminuric renal disease among subjects with advanced stages of chronic kidney failure related to type 2 diabetes mellitus

Urinary albumin excretion has been consistently found to be normal in a significant number of subjects with early stages of diabetic kidney disease. This study was aimed to estimate the prevalence and characteristics of non-albuminuric chronic kidney disease associated with type 2 diabetes mellitus among subjects who reach advanced stages of renal failure. Study population was composed of incident patients with advanced chronic kidney disease (glomerular filtration rate <30?mL/min) related to type 2 diabetes in a tertiary hospital from Gran Canaria (Spain) during a period of 2 years. Subjects were classified as normoalbuminuric (urinary albumin-to-creatine ratio [UACR] <30?mg/g), microalbuminuric (UACR ≥30 and <300?mg/g), or proteinuric (UACR ≥300?mg/g). Of 78 eligible patients, 21.8% had normoalbuminuria, 20.5% had microalbuminuria, and 57.7% had proteinuria. Individuals with normoalbuminuria were mostly women and had a lower prevalence of smoking and polyneuropathy than subjects with microalbuminuria or proteinuria. They also presented greater measures of body mass index and waist circumference, higher values of total and LDL cholesterol, and lower values of HbA_1c and serum creatinine than subjects with microalbuminuria or proteinuria. Multivariate analysis demonstrated that female sex (positively) and HbA_1c and polyneuropathy (negatively) were independently associated with absence of albuminuria. In conclusion, around 20% of subjects with diabetes-related advanced chronic kidney disease, characteristically women, have normal urinary albumin excretion. HbA_1c and polyneuropathy are inversely related to this non-albuminuric form of nephropathy.