Changes in inflammatory markers after sleeve gastrectomy in patients with impaired glucose homeostasis and type 2 diabetes

BackgroundBariatric surgery is an effective treatment for morbid obesity. Obesity and type 2 diabetes are associated with chronic inflammation. There is lack of data examining the effects of sleeve gastrectomy (SG) on inflammatory biomarkers. Our aim was to study the effects of SG on specific cytokines associated with obesity including interleukin-6 (IL-6), interleukin-10 (IL-10), leptin, adiponectin, and C-reactive protein (CRP) preoperatively, 1 and 6 months after surgery.MethodsA nonrandomized prospective study comprising of 22 participants with impaired glucose homeostasis and type 2 diabetes undergoing SG (body mass index 50.1 kg/m², glycated hemoglobin [HbA1c] 53 mmol/mol). Serial measurements of IL-6, IL-10, leptin, adiponectin, and CRP were performed during oral glucose tolerance testing preoperatively, 1 and 6 months postoperatively.ResultsWe observed significant improvements at 1 and 6 months in leptin (P≤.001) and CRP (P = .003) after SG. We also observed a significant reduction in IL-6 at 6 months (P = .001). No statistically significant differences were observed for adiponectin and IL-10.ConclusionThis study is the first to examine the detailed changes in the inflammatory cytokines after SG. Our study shows significant improvements in the inflammatory biomarkers after SG in patients with impaired glucose homeostasis and type 2 diabetes.     

GLP-1 and Changes in Glucose Tolerance following Gastric Bypass Surgery in Morbidly Obese Subjects

Background: It has been proposed, that the dramatic amelioration of type 2 diabetes following Roux-en-Y gastric bypass (RYGBP) could by accounted for, at least in part, by changes in glucagon-like peptide-1 (GLP-1) secretion. However, human data supporting this hypothesis is scarce. Methods: A 12-month prospective study on the changes in glucose homeostasis, and active GLP-1 in response to a standard test meal (STM) was conducted in 34 obese subjects (BMI 49.1±1.0 kg/m²) who had different degrees of glucose tolerance: normal glucose tolerance (NGT, n=12), impaired glucose tolerance (IGT, n=12), and type 2 diabetes (n=10). Results: At 6 weeks after RYGBP, despite the subjects still being markedly obese (BMI 43.5±0.9 kg/m²), fasting plasma glucose and HbA1c decreased in the 3 study groups (P<0.05). Insulin sensitivity improved, but was still abnormal in a comparable proportion of subjects among groups (P=0.717). When insulin secretion was accounted for the prevailing insulin sensitivity, an increase was found in subjects with diabetes (P<0.05) although it remained lower compared to NGT- and IGT-subjects (P<0.01). At 12 months follow-up, no differences among groups were found in the evaluated glucose homeostasis parameters. Compared to baseline, at 6 weeks the incremental AUC_0-120' of active GLP-1 in response to the STM increased in NGT and IGT (P<0.05) but not in subjects with diabetes (P=0.285). However, the GLP-1 response to a STM was comparable among groups at 12 months follow-up (P=0.887). Conclusions: 1) RYGBP was associated with an improvement but not complete restoration of glucose homeostasis at 6 weeks after surgery. 2) GLP-1 is not a critical factor for the early changes in glucose tolerance.     

Effect of Hypoxia on Glucose Metabolism in Nondiabetic Patients With Obstructive Sleep Apnea Syndrome

AimObstructive sleep apnea syndrome (OSAS) may promote hyperglycemia and insulin resistance. Our aim is to investigate the effect of OSAS on the fasting plasma glucose, glycosylated hemoglobin (HbA_1c), and C reactive protein (CRP) in nondiabetic patients.Materials and methodsBlood parameters of consecutive 90 non diabetic patients whom polysomnografic evaluations were done in our sleep laboratory was evaluated. Among these 61 patients with normal fasting blood glucose were classified due to their apne-hipopnea index (AHI) as mild (n=16, 26.2%), moderate (n=18, 29.5%) and severe (n=27, 44.2%) OSAS. The fasting plasma glucose, HbA_1c and CRP were measured.ResultsMean age of the patients was 47.7±11.2 years, 72% male. HbA_1c, fasting glucose levels show positive correlation with BMI (r=.503, P=.00; r=.258, P=.045). No relation of HbA_1c to apnea index nor AHI was detected while positive correlation of fasting glucose and CRP was detected (r=.262, P=.042; r=.258, P=.045). HbA_1c, fasting glucose and CRP levels show negative correlation with minimum SpO₂ levels (by order of r=–.302, P=.018; r=–.368, P=.004; r=–.365, P=.004). HbA1c, fasting glucose levels and CRP levels show positive correlation with mean desaturation index (time duration in which SpO₂<90% by pulse oxymeter) (r=.263, P=.041; r=.311, P=.015; r=.283, P=.027).ConclusionsAlthough no relation in between increased HbA_1c or glucose levels and severity of OSAS was detected in nondiabetic OSAS patients, the correlation with the night hypoxia was detected. This could also show the effect of night time hypoxia on glucose metabolism in OSAS patients.     

Unraveling,contributing factors to the severity of postprandial hypoglycemia after gastric bypass surgery

BackgroundDespite the increasing prevalence of postbariatric hypoglycemia (PBH), a late metabolic complication of bariatric surgery, our understanding of its diverse manifestations remains incomplete.ObjectivesTo contrast parameters of glucose-insulin homeostasis in 2 distinct phenotypes of PBH (mild versus moderate hypoglycemia) based on nadir plasma glucose.SettingUniversity Hospital (Bern, Switzerland).MethodsTwenty-five subjects with PBH following gastric bypass surgery (age, 41 ± 12 years; body mass index, 28.1 ± 6.1kg/m²) received 75g of glucose with frequent blood sampling for glucose, insulin, C-peptide, and glucagon-like peptide 1 (GLP)-1. Based on nadir plasma glucose (</≥50mg/dL), subjects were grouped into level 1 (L1) and level 2 (L2) PBH groups. Beta-cell function (BCF), GLP-1 exposure (λ), beta-cell sensitivity to GLP-1 (π), potentiation of insulin secretion by GLP-1 (PI), first-pass hepatic insulin extraction (HE), insulin sensitivity (SI), and rate of glucose appearance (Ra) were calculated using an oral model of GLP-1 action coupled with the oral minimal model.ResultsNadir glucose was 43.3 ± 6.0mg/dL (mean ± standard deviation) and 60.1 ± 9.1mg/dL in L2- and L1-PBH, respectively. Insulin exposure was significantly higher in L2 versus L1 (P = .004). Mathematical modeling revealed higher BCF in L2 versus L1 (34.3 versus 18.8 10^-91min^-1; P = .003). Despite an increased GLP-1 exposure in L2 compared to L1 PBH (50.7 versus 31.9pmol1L^-11min110²; P = .021), no significant difference in PI was observed (P = .204). No significant differences were observed for HE, Ra, and SI.ConclusionsOur results suggest that higher insulin exposure in PBH patients with lower postprandial nadir glucose values mainly relate to a higher responsiveness to glucose, rather than GLP-1.     

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.     

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.     

Changes in gut hormone profile and glucose homeostasis after laparoscopic sleeve gastrectomy

BackgroundChanges in glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) levels after bariatric surgery have been proposed as a mechanism for long-term maintenance of weight loss and improvement in glucose homeostasis postoperatively. The objective of the present study was to assess the changes in GLP-1, PYY, insulin, and glucose levels after laparoscopic sleeve gastrectomy (SG).MethodsTen morbidly obese patients without type 2 diabetes (3 male, 7 female; body mass index [BMI] 47.92±2.06 kg/m²) were evaluated preoperatively and at 6 weeks, 6 months, and 12 months after SG. Total GLP-1, total PYY, insulin, and glucose were measured in fasting state and every 30 minutes after ingestion of 75 g glucose for a total time of 120 minutes.ResultsBMI decreased markedly postoperatively (P<.001). Postprandial total GLP-1 and total PYY responses, measured by the area under the curve (AUC), were significantly increased by the sixth postoperative week compared with preoperative period (P<.001). Fasting insulin levels were markedly decreased postoperatively at all time points (all P<.01). Insulin AUC decreased progressively throughout the first postoperative year (P = .04), whereas glucose AUC decreased significantly at 6 and 12 months postoperatively (both P<.01). Insulin sensitivity measured by the Matsuda index increased progressively postoperatively. First phase insulin secretion remained unchanged.ConclusionPostprandial total GLP-1 and total PYY levels increased significantly at 6 weeks post-SG and remained elevated for at least 1 year. These findings may indicate their involvement in better glucose homeostasis and weight loss maintenance after SG.     

Hypertriglyceridemia is associated with insulin levels in adult cystic fibrosis patients

BackgroundRecent studies have identified hypertriglyceridemic cystic fibrosis patients (CF-TG). However, whether hypertriglyceridemia is associated with an altered metabolic profile remains unknown.ObjectiveTo characterize CF-TG and determine whether triglycerides (TG) levels are associated with metabolic alterations.Methods210 adult CF subjects from the Montreal Cystic Fibrosis Cohort without known diabetes were included in the analysis. All subjects underwent an OGTT to assess glucose tolerance, insulin secretion (insulin AUC) and insulin sensitivity (Stumvoll index). Fasting lipid profiles, pulmonary function (%FEV₁) and BMI were determined. Hypertriglyceridemia (TG > 1.7 mmol/L) was observed in 20 CF patients. These subjects were matched for age, sex and glucose tolerance category with 20 CF patients (CF-normal-TG) and 20 healthy controls that had TG levels below 1.7 mmol/L. Pearson correlations were performed in the complete study sample (n = 210) to examine the associations between TG levels and other parameters.ResultsThe prevalence of hypertriglyceridemia was 9.5%. Compared to CF-normal-TG, CF-TG subjects displayed significantly higher %FEV_1, insulin AUC (AUC_0–120, AUC_0–30, AUC_30–120), cholesterol levels and a higher ratio of total cholesterol to HDL-cholesterol. Pearson analysis demonstrated that TG levels were associated with BMI, %FEV₁, fasting insulin, insulin AUC_0–120 and AUC_30–120, Stumvoll index, cholesterol levels and the ratio of total cholesterol to HDL-cholesterol. All these correlations remained significant after correction for BMI except %FEV₁.ConclusionTG levels are associated with a mild alteration of the metabolic profile. Whether these changes will increase the long-term risk of CF patients in developing cardiometabolic complications remains to be investigated.     

Long-term remission of type 2 diabetes in morbidly obese patients after sleeve gastrectomy

BackgroundThe aim of this study was to evaluate the long-term effects of laparoscopic sleeve gastrectomy (LSG) on type 2 diabetes mellitus (T2DM) and other related co-morbidities in severely obese patients.MethodsFrom May 2003 to July 2008, 33 morbidly obese diabetic patients (20 with body mass index [BMI]>50 kg/m²) underwent LSG. A total of 23 females and 10 males participated, with a mean age of 49.3±8 years, mean preoperative BMI of 52.1±8.5 kg/m², mean fasting plasma glucose (FPG) of 143.2±47.9 mg/dL, mean glycosylated hemoglobin (HbA_1c) of 7.3%±1.4%, and a mean T2DM duration of 7 years. All patients had a 36-month follow-up, and 13 had a 60-month follow-up.ResultsTwenty-nine patients (87.8%) discontinued antidiabetic medications 3 months after LSG, (mean BMI of 42.8±7.8 kg/m²; FPG of 104.5±22.1 mg/dL; HbA_1c of 5.3%±.4%). At 36 months, 22 of 26 LSG patients (84.6%) had normal FPG and HbA_1c values without antidiabetic therapy. At the 60-month follow-up, 10 of 13 patients (76.9%) had normal FPG and HbA_1c values without antidiabetic therapy. The Framingham risk score decreased significantly from 9.7% preoperatively to 4.7% postoperatively. No new diabetic retinopathy occurred during the whole period of observation.ConclusionsThis study confirms the efficacy of LSG in the treatment of T2DM and indicates that, at both 36- and 60-month follow-ups, LSG can provide a significant percentage of treated patients with a prolonged remission of T2DM, with diminished cardiac risk factors and no development of diabetic retinopathy. These results compare favorably with those reported after standard medical therapy.     

Multiple Nonglycemic Genomic Loci Are Newly Associated With Blood Level of Glycated Hemoglobin in East Asians

Glycated hemoglobin A_1c (HbA_1c) is used as a measure of glycemic control and also as a diagnostic criterion for diabetes. To discover novel loci harboring common variants associated with HbA_1c in East Asians, we conducted a meta-analysis of 13 genome-wide association studies (GWAS; N = 21,026). We replicated our findings in three additional studies comprising 11,576 individuals of East Asian ancestry. Ten variants showed associations that reached genome-wide significance in the discovery data set, of which nine (four novel variants at TMEM79 [P value = 1.3 × 10⁻²³], HBS1L/MYB [8.5 × 10⁻¹⁵], MYO9B [9.0 × 10⁻¹²], and CYBA [1.1 × 10⁻⁸] as well as five variants at loci that had been previously identified [CDKAL1, G6PC2/ABCB11, GCK, ANK1, and FN3KI]) showed consistent evidence of association in replication data sets. These variants explained 1.76% of the variance in HbA_1c. Several of these variants (TMEM79, HBS1L/MYB, CYBA, MYO9B, ANK1, and FN3K) showed no association with either blood glucose or type 2 diabetes. Among individuals with nondiabetic levels of fasting glucose (<7.0 mmol/L) but elevated HbA_1c (≥6.5%), 36.1% had HbA_1c <6.5% after adjustment for these six variants. Our East Asian GWAS meta-analysis has identified novel variants associated with HbA_1c as well as demonstrated that the effects of known variants are largely transferable across ethnic groups. Variants affecting erythrocyte parameters rather than glucose metabolism may be relevant to the use of HbA_1c for diagnosing diabetes in these populations.     

Efficacy and safety of vildagliptin/pioglitazone combination therapy in Korean patients with diabetes

AIM: To assess the efficacy and safety of vildagliptin/pioglitazone combination therapy in Korean patients with type 2 diabetes mellitus (T2DM).METHODS: This was a post hoc analysis in Korean patients, from a 24-wk, randomized, active-controlled, double-blind, parallel-group, multicenter study. Eligible patients were aged between 18 and 80 years, drug naive, and had been diagnosed with T2DM [hemoglobin A_1c (HbA_1c): 7.5%-11.0% and fasting plasma glucose (FPG): < 270 mg/dL (< 15 mmol/L)]. Patients were randomized (1:1:1:1) to receive the vildagliptin/pioglitazone combination at 100/30 mg q.d. (high-dose) or 50/15 mg q.d. (low-dose), vildagliptin 100 mg q.d., or pioglitazone 30 mg q.d. monotherapies. The primary outcome measure was change in HbA_1c from baseline to endpoint.RESULTS: The distribution of baseline demographic and clinical parameters was well balanced between treatment groups. The overall mean age, body mass index, HbA_1c, FPG, and duration of disease were 50.8 years, 24.6 kg/m², 8.6%, 10.1 mmol/L, and 2.2 years, respectively. Adjusted mean changes (± standard error) in HbA_1c from baseline (~8.7%) to week 24 endpoint were -2.03% ± 0.16% (high-dose, N = 34), -1.88% ± 0.15% (low-dose, N = 34), -1.31% ± 0.21% (vildagliptin, N = 36), and -1.52% ± 0.16% (pioglitazone, N = 36). The high-dose combination therapy demonstrated greater efficacy than monotherapies [vildagliptin (P = 0.029) and pioglitazone (P = 0.027)]. Percentage of patients achieving HbA_1c < 7% and ≤ 6.5% was the highest in the high-dose group (76% and 68%) followed by low-dose (58% and 47%), vildagliptin (59% and 37%), and pioglitazone (53% and 28%) groups. The overall incidence of adverse events was comparable.CONCLUSION: In Korean patients, first-line treatment with high-dose combination therapy improved glycemic control compared to pioglitazone and vildagliptin monotherapies, consistent with results published for the overall study population.     

Update on pre-diabetes: Focus on diagnostic criteria and cardiovascular risk

Pre-diabetes, which is typically defined as blood glucose concentrations higher than normal but lower than the diabetes threshold, is a high-risk state for diabetes and cardiovascular disease development. As such, it represents three groups of individuals: Those with impaired fasting glucose (IFG), those with impaired glucose tolerance (IGT) and those with a glycated haemoglobin (HbA_1c) between 39-46 mmol/mol. Several clinical trials have shown the important role of IFG, IGT and HbA_1c-pre-diabetes as predictive tools for the risk of developing type 2 diabetes. Moreover, with regard to cardiovascular disease, pre-diabetes is associated with more advanced vascular damage compared with normoglycaemia, independently of confounding factors. In view of these observations, diagnosis of pre-diabetes is mandatory to prevent or delay the development of the disease and its complications; however, a number of previous studies reported that the concordance between pre-diabetes diagnoses made by IFG, IGT or HbA_1c is scarce and there are conflicting data as to which of these methods best predicts cardiovascular disease. This review highlights recent studies and current controversies in the field. In consideration of the expected increased use of HbA_1c as a screening tool to identify individuals with alteration of glycaemic homeostasis, we focused on the evidence regarding the ability of HbA_1c as a diagnostic tool for pre-diabetes and as a useful marker in identifying patients who have an increased risk for cardiovascular disease. Finally, we reviewed the current evidence regarding non-traditional glycaemic biomarkers and their use as alternatives to or additions to traditional ones.     

Endoscopic Duodenal–Jejunal Bypass Liner Rapidly Improves Type 2 Diabetes

Background

Bariatric procedures excluding the proximal small intestine improve glycemic control in type 2 diabetes within days. To gain insight into the mediators involved, we investigated factors regulating glucose homeostasis in patients with type 2 diabetes treated with the novel endoscopic duodenal–jejunal bypass liner (DJBL).

Methods

Seventeen obese patients (BMI 30–50 kg/m²) with type 2 diabetes received the DJBL for 24 weeks. Body weight and type 2 diabetes parameters, including HbA_1c and plasma levels of glucose, insulin, glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), and glucagon, were analyzed after a standard meal before, during, and 1 week after DJBL treatment.

Results

At 24 weeks after implantation, patients had lost 12.7?±?1.3 kg (p?<?0.01), while HbA_1c had improved from 8.4?±?0.2 to 7.0?±?0.2 % (p?<?0.01). Both fasting glucose levels and the postprandial glucose response were decreased at 1 week after implantation and remained decreased at 24 weeks (baseline vs. week 1 vs. week 24: 11.6?±?0.5 vs. 9.0?±?0.5 vs. 8.6?±?0.5 mmol/L and 1,999?±?85 vs. 1,536?±?51 vs. 1,538?±?72 mmol/L/min, both p?<?0.01). In parallel, the glucagon response decreased (23,762?±?4,732 vs. 15,989?±?3,193 vs. 13,1207?±?1,946 pg/mL/min, p?<?0.05) and the GLP-1 response increased (4,440?±?249 vs. 6,407?±?480 vs. 6,008?±?429 pmol/L/min, p?<?0.01). The GIP response was decreased at week 24 (baseline—115,272?±?10,971 vs. week 24—88,499?±?10,971 pg/mL/min, p?<?0.05). Insulin levels did not change significantly. Glycemic control was still improved 1 week after explantation.

Conclusions

The data indicate DJBL to be a promising treatment for obesity and type 2 diabetes, causing rapid improvement of glycemic control paralleled by changes in gut hormones.     

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.     

Early glucose abnormalities are associated with pulmonary inflammation in young children with cystic fibrosis

BackgroundChildren with CF are insulin deficient from infancy but very little is known about the impact of glucose abnormalities in early life. We aimed to identify and describe interstitial glucose levels in CF children <6 years and to evaluate the association with pulmonary infection and inflammation.MethodsWe assessed 18 children (5 females) with median age of 3.2 years (range 0·9–5.5) with Continuous Glucose Monitoring for 3 days. Bronchoalveolar lavage (BAL) fluid was cultured for known pathogenic microbial agents and assessed for total white blood cells, percentage of neutrophils and IL-8 level.ResultsPeak sensor glucose (SG) was >11.1 mmol/L in 39% of participants. The percentage neutrophil count on BAL was positively correlated with elevated SG (peak SG r_s = 0.48, p = .044) and with glucose variability (SG standard deviation r = 0.62, β = 38.5, p = .006). BAL IL-8 level was significantly correlated with all measures of CGM hyperglycemia including % time > 7.8 mmol/L (p = .008) and standard deviation (p < .001). Participants with a history of Pseudomonas aeruginosa had a higher % time > 7.8 mmol/L glucose (16% versus 3%, p = .015).ConclusionChildren with CF frequently demonstrate elevated SG levels before age 6 years, which are associated with increased pulmonary inflammation and Pseudomonas aeruginosa infection. Transient SG elevations into the diabetic range (≥11.1 mmol/L) were identified in children from 1 year of age.     

GLP-1 Cleavage Product Reverses Persistent ROS Generation After Transient Hyperglycemia by Disrupting an ROS-Generating Feedback Loop

The assumption underlying current diabetes treatment is that lowering the level of time-averaged glucose concentrations, measured as HbA_1c, prevents microvascular complications. However, 89% of variation in risk of retinopathy, microalbuminuria, or albuminuria is due to elements of glycemia not captured by mean HbA_1c values. We show that transient exposure to high glucose activates a multicomponent feedback loop that causes a stable left shift of the glucose concentration-reactive oxygen species (ROS) dose-response curve. Feedback loop disruption by the GLP-1 cleavage product GLP-1(9–36)^amide reverses the persistent left shift, thereby normalizing persistent overproduction of ROS and its pathophysiologic consequences. These data suggest that hyperglycemic spikes high enough to activate persistent ROS production during subsequent periods of normal glycemia but too brief to affect the HbA_1c value are a major determinant of the 89% of diabetes complications risk not captured by HbA_1c. The phenomenon and mechanism described in this study provide a basis for the development of both new biomarkers to complement HbA_1c and novel therapeutic agents, including GLP-1(9–36)^amide, for the prevention and treatment of diabetes complications.     

Relationship between biochemical and symptomatic hypoglycemia after RYGB. Responses to a mixed meal test: a case-control study

BackgroundPostprandial hypoglycemia is a relatively common complication after Roux-en-Y gastric bypass (RYGB). The cause remains incompletely understood, and the association between biochemical hypoglycemia and hypoglycemic symptoms is unclear.ObjectivesTo evaluate the association between postprandial hormonal responses and biochemical and symptomatic hypoglycemia after RYGB.SettingUniversity Hospital, Denmark.MethodsA case-control study with 3 groups: (1) RYGB group with postprandial hypoglycemic symptoms (HS), n = 13; (2) RYGB-group with no symptoms of hypoglycemia (NHS), n = 13; and (3) nonoperated body mass index–matched controls (CON), n = 7. Plasma glucose (PG) and hormonal responses (insulin, glucagon-like peptide-1, gastric inhibitory polypeptide, glucagon) were measured after a mixed meal test (MMT), and hypoglycemic symptoms were determined by a questionnaire. The primary outcomes were differences in subjective and biochemical responses related to hypoglycemia among the 3 groups.ResultsNadir PG was lower (3.1 versus 4.0 mmol/L (56 versus 72 mg/dL); P = .0002) and peak insulin higher in HS than NHS patients (1073 versus 734 pmol/L; P = .0499). Of the 13 patients with a peak insulin >850 pmol/L, 8 patients developed symptoms whereas only 2 out of the 13 patients with peak insulin ≤850 pmol/L developed symptoms, corresponding to an odds ratio of 12 (1.8; 81.7). Post hoc analyses comparing all RYGB patients with biochemical hypoglycemia after the MMT (nadir glucose ≤3.0 mmol/L [54 mg/dL]) with those with glucose >3 mmol/L (54 mg/dL) revealed a difference in both peak insulin (1138 versus 760 pmol/L; P = .042) and peak glucagon-like peptide-1 (182 versus 86 pmol/L; P = .016) concentrations.ConclusionsPatients with HS had lower nadir PG and higher insulin responses than NHS patients after MMT. Regarding PG, PG ≤3.0 mmol/L (54 mg/dL) was the best discriminator of having hypoglycemic symptoms after the MMT. However, high insulin level seems the most important predictor for having both biochemical and symptomatic hypoglycemia.     

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.     

Importance of Small Bowel Peptides for the Improved Glucose Metabolism 20 Years after Jejunoileal Bypass for Obesity

Background: Obese patients operated with jejunoileal bypass (JIB) have reduced plasma concentrations of insulin and glucose. Gastric inhibitory peptide/glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1) have been found to have a profound incretin effect in humans. The aim of the present study was to examine the long-term effect of JIB on glucose metabolism. Methods: Four groups (lean, nonoperated obese, obese 9 months after JIB and obese 20 years after JIB) of six females each were given a mixed meal (280 kcal). Plasma samples were obtained every 10 min for 60 min postprandially and were analyzed for glucose, insulin, GIP and GLP-1. Results: A reduction in body mass index (kg/m²) was seen for the two patient groups operated with JIB (12.1, at 9 months post-op; 13.1, at 20 years post-op). Surgery by JIB resulted in a reduction of glucose and insulin values. Concomitantly there was an elevation of postprandial GIP and GLP-1 plasma concentrations. In the obese subjects 20 years after JIB both fasting and postprandial GIP and GLP-1 values were markedly elevated compared with the other three groups; and plasma glucose and insulin concentrations were maintained at normal levels. Conclusions: The improvement in glucose metabolism seen after JIB may be due to reduced insulin resistance after weight loss and/or increased levels of the incretin hormones GIP and GLP-1. Progressively, elevated levels of GIP and GLP-1 seem to be necessary to maintain glucose homeostasis at longterm follow-up after this procedure.     

Preserved Insulin Secretory Capacity and Weight Loss Are the Predominant Predictors of Glycemic Control in Patients With Type 2 Diabetes Randomized to Roux-en-Y Gastric Bypass

Improvement in type 2 diabetes after Roux-en-Y gastric bypass (RYGB) has been attributed partly to weight loss, but mechanisms beyond weight loss remain unclear. We performed an ancillary study to the Diabetes Surgery Study to assess changes in incretins, insulin sensitivity, and secretion 1 year after randomization to lifestyle modification and intensive medical management (LS/IMM) alone (n = 34) or in conjunction with RYGB (n = 34). The RYGB group lost more weight and had greater improvement in HbA_1c. Fasting glucose was lower after RYGB than after LS/IMM, although the glucose area under the curve decreased comparably for both groups. Insulin sensitivity increased in both groups. Insulin secretion was unchanged after LS/IMM but decreased after RYGB, except for a rapid increase during the first 30 min after meal ingestion. Glucagon-like peptide 1 (GLP-1) was substantially increased after RYGB, while gastric inhibitory polypeptide and glucagon decreased. Lower HbA_1c was most strongly correlated with the percentage of weight loss for both groups. At baseline, a greater C-peptide index and 90-min postprandial C-peptide level were predictive of lower HbA_1c at 1 year after RYGB. β-Cell glucose sensitivity, which improved only after RYGB, and improved disposition index were associated with lower HbA_1c in both groups, independent of weight loss. Weight loss and preserved β-cell function both predominantly determine the greatest glycemic benefit after RYGB.