Martin G. Bischof

Long-chain n−3 PUFAs reduce adipose tissue and systemic inflammation in severely obese nondiabetic patients: a randomized controlled trial

BACKGROUND Chronic adipose tissue inflammation is a hallmark of obesity, triggering the development of associated pathologies, particularly type 2 diabetes. Long-chain n-3 PUFAs reduce cardiovascular events and exert well-established antiinflammatory effects, but their effects on human adipose tissue inflammation are unknown. OBJECTIVE We investigated whether n-3 PUFAs reduce adipose tissue inflammation in severely obese nondiabetic patients. DESIGN We treated 55 severely obese nondiabetic patients, scheduled to undergo elective bariatric surgery, with 3.36 g long-chain n-3 PUFAs/d (EPA, DHA) or an equivalent amount of butterfat as control, for 8 wk, in a randomized open-label controlled clinical trial. The primary efficacy measure was inflammatory gene expression in visceral and subcutaneous adipose tissue samples (subcutaneous adipose tissue and visceral adipose tissue), collected during surgery after the intervention. Secondary efficacy variables were adipose tissue production of antiinflammatory n-3 PUFA-derived eicosanoids, plasma concentrations of inflammatory markers, metabolic control, and the effect of the Pro12Ala PPARG polymorphism on the treatment response. RESULTS Treatment with n-3 PUFAs, which was well tolerated, decreased the gene expression of most analyzed inflammatory genes in subcutaneous adipose tissue (P < 0.05) and increased production of antiinflammatory eicosanoids in visceral adipose tissue and subcutaneous adipose tissue (P < 0.05). In comparison with control subjects who received butterfat, circulating interleukin-6 and triglyceride concentrations decreased significantly in the n-3 PUFA group (P = 0.04 and P = 0.03, respectively). The Pro12Ala polymorphism affected the serum cholesterol response to n-3 PUFA treatment. CONCLUSIONS Treatment with long-chain n-3 PUFAs favorably modulated adipose tissue and systemic inflammation in severely obese nondiabetic patients and improved lipid metabolism. These effects may be beneficial in the long-term treatment of obesity. This trial was registered at clinicaltrials.gov as NCT00760760.

Alterations in Gastrointestinal, Endocrine, and Metabolic Processes After Bariatric Roux-en-Y Gastric Bypass Surgery

OBJECTIVE Obesity leads to severe long-term complications and reduced life expectancy. Roux-en-Y gastric bypass (RYGB) surgery induces excessive and continuous weight loss in (morbid) obesity, although it causes several abnormal anatomical and physiological conditions. RESEARCH DESIGN AND METHODS To distinctively unveil effects of RYGB surgery on β-cell function and glucose turnover in skeletal muscle, liver, and gut, nondiabetic, morbidly obese patients were studied before (pre-OP, five female/one male, BMI: 49 ± 3 kg/m2, 43 ± 2 years of age) and 7 ± 1 months after (post-OP, BMI: 37 ± 3 kg/m2) RYGB surgery, compared with matching obese (CONob, five female/one male, BMI: 34 ± 1 kg/m2, 48 ± 3 years of age) and lean controls (CONlean, five female/one male, BMI: 22 ± 0 kg/m2, 42 ± 2 years of age). Oral glucose tolerance tests (OGTTs), hyperinsulinemic-isoglycemic clamp tests, and mechanistic mathematical modeling allowed determination of whole-body insulin sensitivity (M/I), OGTT and clamp test β-cell function, and gastrointestinal glucose absorption. RESULTS Post-OP lost (P < 0.0001) 35 ± 3 kg body weight. M/I increased after RYGB, becoming comparable to CONob, but remaining markedly lower than CONlean (P < 0.05). M/I tightly correlated (τ = −0.611, P < 0.0001) with fat mass. During OGTT, post-OP showed ≥15% reduced plasma glucose from 120 to 180 min (≤4.5 mmol/L), and 29-fold elevated active glucagon-like peptide-1 (GLP-1) dynamic areas under the curve, which tightly correlated (r = 0.837, P < 0.001) with 84% increased β-cell secretion. Insulinogenic index (0–30 min) in post-OP was ≥29% greater (P < 0.04). At fasting, post-OP showed approximately halved insulin secretion (P < 0.05 vs. pre-OP). Insulin-stimulated insulin secretion in post-OP was 52% higher than before surgery, but 1–2 pmol/min2 lower than in CONob/CONlean (P < 0.05). Gastrointestinal glucose absorption was comparable in pre-OP and post-OP, but 9–26% lower from 40 to 90 min in post-OP than in CONob/CONlean (P < 0.04). CONCLUSIONS RYGB surgery leads to decreased plasma glucose concentrations in the third OGTT hour and exaggerated β-cell function, for which increased GLP-1 release seems responsible, whereas gastrointestinal glucose absorption remains unchanged but lower than in matching controls.

Sex-Specific Differences in Glycemic Control and Cardiovascular Risk Factors in Older Patients With Insulin-Treated Type 2 Diabetes Mellitus

BACKGROUND Because women have been excluded from many study populations in investigations of diabetes care, there is insufficient information on sex-specific differences in glycemic control. OBJECTIVE The aim of the present study was to assess whether treatment goals for glycemic and cardiovascular risk factor control are achieved equally in older, Central European, female and male patients with type 2 diabetes mellitus (T2DM). METHODS In a retrospective cross-sectional study, data were analyzed from consecutive older (aged ≥60 years) female and male patients with insulin-treated T2DM who attended a diabetes outpatient clinic between January 2007 and April 2008 at the Medical University of Vienna, Austria. Sex-specific differences in glycosylated hemoglobin (HbA₁(c)) levels were assessed as the primary outcome. LDL-C and HDL-C, as well as systolic and diastolic blood pressure (SBP and DBP, respectively), were assessed as secondary outcomes and were adjusted for age, duration of diabetes, duration of insulin treatment, body mass index, insulin units per kilogram per day, and secondary causes of diabetes. P values were adjusted using the Bonferroni correction. RESULTS Data were analyzed from 183 female and 209 male patients with insulin-treated T2DM. In multivariate linear regression models, women had significantly higher levels of LDL-C (P = 0.008), HDL-C (P < 0.001), SBP (P < 0.001), and DBP (P = 0.034), but not HbA₁(c) (P = NS). Multivariate logistic regression models revealed that women were significantly less likely to meet treatment goals for blood pressure (SBP, P = 0.044; DBP, P = 0.024), but not for cholesterol or HbA₁(c) levels (P = NS for LDL-C, HDL-C, and HbA₁(c)). CONCLUSION In this study of older patients with insulin-treated T2DM, whereas glycemic control was comparable between women and men, a more adverse cardiovascular risk factor profile was observed in female patients.

Effects of Gastric Bypass Surgery on Insulin Resistance and Insulin Secretion in Nondiabetic Obese Patients

Roux‐en‐Y‐Gastric‐Bypass (RYGB) reduces overall and diabetes‐specific mortality by 40% and over 90%. This study aims to gain insight into the underlying mechanisms of this effect. We evaluated time‐courses of glucose, insulin, C‐peptide, and the incretin glucagon like peptide‐1 (GLP‐1) following an oral glucose load. Insulin‐sensitivity was measured by a hyperinsulinemic‐isoglycemic‐clamp‐test; glucose‐turnover was determined using d‐[6,6‐2H2] glucose. Examinations were performed in six nondiabetic patients with excess weight before (PRE: BMI: 49.3 ± 3.2 kg/m2) and 7 months after RYGB (POST: BMI: 36.7 ± 2.9 kg/m2), in a lean (CON: BMI: 22.6 ± 0.6 kg/m2) and an obese control group (CONob) without history of gastrointestinal surgery (BMI: 34.7 ± 1.2 kg/m2). RYGB reduced fasting plasma concentrations of insulin and C‐peptide (P < 0.01, respectively) whereas fasting glucose concentrations remained unchanged. After RYGB increase of C‐peptide concentration following glucose ingestion was significantly higher compared to all other groups (dynamic‐area under the curve (Dyn‐AUC): 0–90 min: POST: 984 ± 115 ng·min/ml, PRE: 590 ± 67 ng·min/ml, CONob: 440 ± 44 ng·min/ml, CON: 279 ± 22 ng·min/ml, P < 0.01 respectively). Early postprandial increase of glucose concentration was however not affected. GLP‐1 concentrations following glucose ingestion were sixfold higher after RYBG than before (P = 0.01). Insulin‐stimulated glucose uptake tended to increase postoperatively (M‐value: PRE: 1.8 ± 0.5, POST: 3.0 ± 0.3, not significant (n.s.)). Endogenous glucose production (EGP) was unaffected by RYGB. Hepatic insulin resistance index improved after RYGB and was then comparable to both control groups (PRE: 29.2 ± 4.3, POST: 12.6 ± 1.1, P < 0.01). RYGB results in hyper‐secretion of insulin and C‐peptide, whereas improvements of insulin resistance are minor and seem to occur rather in the liver and the adipose tissue than in the skeletal muscle.

Glucose turnover and intima media thickness of internal carotid artery in type 2 diabetes offspring

Background  First‐degree offspring (OFF) of type 2 diabetic (T2DM) patients bear a ~40% lifetime risk of developing T2DM. They are insulin resistant and carry a risk of premature atherosclerosis, the extent of which can be estimated by intima media thickness (IMT) of the carotid artery (CA). Thus, this study examines parameters of glucose and lipid metabolism, insulin sensitivity, beta cell function (BCF) and IMT with their interrelationships in middle‐aged OFF.

Cerebral glutamate metabolism during hypoglycaemia in healthy and type 1 diabetic humans

Background  The mechanisms responsible for the progressive failure of hypoglycaemia counterregulation in long‐standing type 1 diabetes are poorly understood. Increased brain glucose uptake during hypoglycaemia or alterations of brain energy metabolism could effect glucose sensing by the brain and thus contribute to hypoglycaemia‐associated autonomic failure.

Persistent arterial stiffness and endothelial dysfunction following successful pancreas–kidney transplantation in Type 1 diabetes

Objective  Successful simultaneous pancreas‐kidney transplantation (SPK) in Type 1 diabetic (T1DM) patients results in improved cardiovascular outcome and survival. However, it is doubtful whether the impairment of cardiovascular and endothelial function in T1DM can be completely reversed.

Long-term impact of a structured group-based inpatient-education program for intensive insulin therapy in patients with diabetes mellitus.

ZusammenfassungSTUDIENZIEL: Strukturierte Patientenschulungen können über die Vermittlung von Eigenkompetenz und Fachwissen an den Patienten einen positiven Einfluss auf die individuelle Krankheitsentwicklung von insulinabhängigen Diabetikern haben. Im Rahmen dieser Studie soll der Effekt eines Schulungsprogramms auf Stoffwechselparameter bei insulinabhängigem Diabetes untersucht werden. Daneben sollen mögliche Unterschiede für bestimmte Subgruppen herausgearbeitet werden. METHODIK: In eine retrospektive longitudinale Studie wurden 81 Patienten eingeschlossen (59 Typ 1 Diabetes, 14 Typ 2 Diabetes, 8 andere Formen), die zwischen den Jahren 2003 und 2005 an einem achttägigen Schulungsprogramm an der Universitätsklinik für Innere Medizin III teilnahmen. HbA1c-, LDL-Cholesterin-, HDL-Cholesterin- und BMI-Werte wurden 0 – 15 Monate vor, sowie 0 – 5, 5 – 10 und 10 – 20 Monate nach der Schulung ermittelt. ERGEBNISSE: Unmittelbar nach erfolgter Schulung (0 – 5 Monate) zeigte das Studienkollektiv eine vorübergehende Abnahme von HbA1c (0,2 %, 95 % CI: 0,04 – 0,37, P = 0,017) und LDL-Cholesterin (9,95 mg/dl, 95 % CI: 2,24 – 17,76, P = 0,013). Im weiteren Verlauf kehrten die Werte wieder zum Ausgangsniveau zurück. Daneben war eine kontinuierliche Verbesserung im HDL-Cholesterin feststellbar (P = 0,025). Keine zeitabhängige Veränderung zeigte sich dagegen im BMI. Eine signifikante Interaktion zwischen Beobachtungszeit und Diabetesformen (P = 0,008) in der multivariablen Analyse lässt besonders für Typ 2 Diabetiker einen Langzeit-Vorteil vermuten. SCHLUSSFOLGERUNG: Durch strukturierte Patientenschulungen kann vorübergehend eine moderate Verbesserung im Blutzucker- und Cholesterin-Profil erreicht werden. Eine günstige Langzeit-Auswirkung wird für HDL-Cholesterin sowie bei Patienten mit Typ 2 Diabetes für HbA1c gezeigt.SummaryPURPOSE: Structured patient education aiming to improve self-management strategies might be beneficial for insulin-treated diabetic patients. However, in previous studies the extent of the benefit has been inconsistent in different subgroups of patients. The aim of the present study was to assess the potential benefit of a structured inpatient-education program for intensive insulin therapy according to the basal-bolus concept with particular emphasis on self-management strategies. METHODS: We included 81 diabetic patients (59 with type 1, 14 with type 2, eight with other forms) in this retrospective longitudinal study; all had completed the training program on eight consecutive days at a university clinic between 2003 and 2005. Data assessment included HbA1c, LDL-cholesterol, HDL-cholesterol and BMI at baseline (0–15 months before the training) and after 0–5, 5–10 and 10–20 months. RESULTS: A transient decrease of HbA1c (0.2%, 95% CI: 0.04–0.37, P = 0.017) and LDL-cholesterol levels (9.95 mg/dl, 95% CI: 2.24–17.76, P = 0.013) between baseline and the first follow-up examination was observed in the group overall. Thereafter, HbA1c and LDL-cholesterol were similar to baseline, whereas a persistent increase in HDL-cholesterol (P = 0.025) was evident in the multivariable analysis. No changes in BMI were observed. A significant type-by-time interaction (P = 0.008) in HbA1c suggests a long-term benefit in glycemic control in patients with type 2 diabetes. CONCLUSION: A diabetes training program for intensive insulin therapy with particular emphasis on self-management skills was followed by a moderate and transient improvement of glycemic control and LDL-cholesterol and by a persistent increase in HDL-cholesterol. Long-term improvement in glycemic control was observed only in patients with type 2 diabetes.

Fasting and postprandial liver glycogen content in patients with type 1 diabetes mellitus after successful pancreas–kidney transplantation with systemic venous insulin delivery

In patients with type 1 diabetes mellitus (T1DM), insulin is usually replaced systemically (subcutaneously) and not via the physiological portal route. According to previous studies, the livers capacity to store glycogen is reduced in T1DM patients, but it remains unclear whether this is due to hyperglycaemia, or whether the route of insulin supply could contribute to this phenomenon. T1DM patients after successful pancreas–kidney transplantation with systemic venous drainage (T1DM‐PKT) represent a suitable human model to further investigate this question, because they are normoglycaemic, but their liver receives insulin from the pancreas transplant via the systemic route.