Kjeld Hermansen

Substituting dietary saturated for monounsaturated fat impairs insulin sensitivity in healthy men and women: The KANWU study

Aims/hypothesis. The amount and quality of fat in the diet could be of importance for development of insulin resistance and related metabolic disorders. Our aim was to determine whether a change in dietary fat quality alone could alter insulin action in humans. Methods. The KANWU study included 162 healthy subjects chosen at random to receive a controlled, isoenergetic diet for 3 months containing either a high proportion of saturated (SAFA diet) or monounsaturated (MUFA diet) fatty acids. Within each group there was a second assignment at random to supplements with fish oil (3.6 g n-3 fatty acids/d) or placebo. Results. Insulin sensitivity was significantly impaired on the saturated fatty acid diet (-10 %, p = 0.03) but did not change on the monounsaturated fatty acid diet ( + 2 %, NS) (p = 0.05 for difference between diets). Insulin secretion was not affected. The addition of n-3 fatty acids influenced neither insulin sensitivity nor insulin secretion. The favourable effects of substituting a monounsaturated fatty acid diet for a saturated fatty acid diet on insulin sensitivity were only seen at a total fat intake below median (37E %). Here, insulin sensitivity was 12.5 % lower and 8.8 % higher on the saturated fatty acid diet and monounsaturated fatty acid diet respectively (p = 0.03). Low density lipoprotein cholesterol (LDL) increased on the saturated fatty acid diet ( + 4.1 %, p < 0.01) but decreased on the monounsaturated fatty acid diet (MUFA) (–5.2, p < 0.001), whereas lipoprotein (a) [Lp(a)] increased on a monounsaturated fatty acid diet by 12 % (p < 0.001). Conclusions/interpretation. A change of the proportions of dietary fatty acids, decreasing saturated fatty acid and increasing monounsaturated fatty acid, improves insulin sensitivity but has no effect on insulin secretion. A beneficial impact of the fat quality on insulin sensitivity is not seen in individuals with a high fat intake ( > 37E %). [Diabetologia (2001) 44: 312–319]

The role of reducing intakes of saturated fat in the prevention of cardiovascular disease: where does the evidence stand in 2010?

Current dietary recommendations advise reducing the intake of saturated fatty acids (SFAs) to reduce coronary heart disease (CHD) risk, but recent findings question the role of SFAs. This expert panel reviewed the evidence and reached the following conclusions: the evidence from epidemiologic, clinical, and mechanistic studies is consistent in finding that the risk of CHD is reduced when SFAs are replaced with polyunsaturated fatty acids (PUFAs). In populations who consume a Western diet, the replacement of 1% of energy from SFAs with PUFAs lowers LDL cholesterol and is likely to produce a reduction in CHD incidence of ≥2-3%. No clear benefit of substituting carbohydrates for SFAs has been shown, although there might be a benefit if the carbohydrate is unrefined and has a low glycemic index. Insufficient evidence exists to judge the effect on CHD risk of replacing SFAs with MUFAs. No clear association between SFA intake relative to refined carbohydrates and the risk of insulin resistance and diabetes has been shown. The effect of diet on a single biomarker is insufficient evidence to assess CHD risk. The combination of multiple biomarkers and the use of clinical endpoints could help substantiate the effects on CHD. Furthermore, the effect of particular foods on CHD cannot be predicted solely by their content of total SFAs because individual SFAs may have different cardiovascular effects and major SFA food sources contain other constituents that could influence CHD risk. Research is needed to clarify the role of SFAs compared with specific forms of carbohydrates in CHD risk and to compare specific foods with appropriate alternatives.

Effects of dietary saturated, monounsaturated and n-3 fatty acids on fasting lipoproteins, LDL size and post-prandial lipid metabolism in healthy subjects.

BACKGROUND The influence of the quality of dietary fat on some aspects of lipid metabolism-i.e. lipoprotein concentrations, post-prandial lipids and LDL size-is not completely understood, especially in healthy individuals. OBJECTIVES Aim of this study was to evaluate the effects of different types of dietary fat (monounsaturated vs. saturated fatty acids, and n-3 or placebo supplementation) on fasting lipoproteins, LDL size and post-prandial lipids in healthy people. DESIGN One hundred and sixty-two individuals were randomly assigned to follow two isoenergetic diets, one rich in saturated fatty acids (SFA diet) and the other in monounsaturated fatty acids (MUFA diet). Each group was further randomised to receive supplementation with fish oil (3.6 g/day) or placebo. RESULTS The type of diet significantly affected LDL cholesterol and triacylglycerol content, which was higher with the SFA diet and lower with the MUFA diet. The changes between the two diets were statistically significant for cholesterol (P<0.01) and triacylglycerol (P<0.03). VLDL cholesterol and triacylglycerol were significantly reduced and LDL cholesterol significantly increased by fish oil supplementation. Plasma triacylglycerol was significantly lower in those taking n-3 fatty acids, also 1 and 3 h after a test-meal. Neither type of diet nor n-3 supplementation affected LDL size. CONCLUSIONS A moderate substitution of saturated fatty acids with monounsaturated fatty acids has beneficial effects on lipid metabolism also in healthy individuals. A moderate supplementation of long-chain n-3 fatty acids in healthy individuals reduces both fasting and post-prandial triacylglycerol concentrations but increases LDL cholesterol, irrespective of the type of diet.

Calcium, glucose and glucagon release

SummaryUsing the isolated, perfused canine pancreas the importance of calcium for the normal secretory function of the pancreatic alpha cell was investigated. It was found that 1. increases in perfusate Ca++ from 1.3 to 4.8 mM and from 1.3 to 8.2 mM during perfusion with glucose concentrations of 25 and 150 mg/100 ml stimulate the release of both glucagon and insulin in a dose-related and a glucose-dependent fashion. The hormone responses to increases in calcium were, with few exceptions, biphasic 2. a ‘Ca++ free’ medium inhibited release of both hormones, and increases in perfusate glucose from 25 to 150 mg/100 ml were unable to suppress glucagon or to stimulate insulin. Addition of calcium (8.2 mM) resulted in re-establishment of the normal regulatory role of glucose upon release of both hormones, now being in a hyperactivated state by the high Ca++ concentration; 3. sudden Ca++ depletion of the perfusate from 2 mM at a glucose concentration of 200 mg/100 ml inhibited immediately the release of both hormones to very low levels, which remained low until the addition of Ca++ (2 mM). Ca++ is therefore an essential requirement for the normal secretory process of pancreatic glucagon, possibly involving uptake and accumulation within the A cell, as established for the B cell. It is suggested that Ca++ exerts its effect on the microtubular microfilamentous system.

Low-intensity training dissociates metabolic from aerobic fitness

This study investigated the effect of prolonged whole‐body low‐intensity exercise on blood lipids, skeletal muscle adaptations and aerobic fitness. Seven male subjects completed a 32‐day crossing of the Greenland icecap on cross‐country skies and before and after this arm or leg cranking was performed on two separate days and biopsies were obtained from arm and leg muscle, and venous blood was sampled.

Differential sensitivity to somatostatin of pancreatic polypeptide, glucagon and insulin secretion from the isolated perfused canine pancreas

This dose-response study deals with the relative inhibitory effect of somatostatin on the acetylcholine-stimulated release of pancreatic polypeptide (PP), glucagon, and insulin from the isolated canine pancrease. Somatostatin in picomolar doses potently inhibited insulin and glucagon secretion, whereas PP secretion was relatively insensitive. Also, in the absence of acetylcholine, somatostatin exerted a preferential inhibition of the release insulin and glucagon compared with PP. These findings point to a physiologically important role of somatostatin for the secretion of insulin and glucagon, but probably not for PP.

Acute Effects of Dietary Fat on Inflammatory Markers and Gene Expression in First-Degree Relatives of Type 2 Diabetes Patients

BACKGROUND Subjects with type 2 diabetes (T2D) and their relatives (REL) carry an increased risk of cardiovascular disease (CVD). Low-grade inflammation, an independent risk factor for CVD, is modifiable by diet. Subjects with T2D show elevated postprandial inflammatory responses to fat-rich meals, while information on postprandial inflammation in REL is sparse. AIM To clarify whether medium-chain saturated fatty acids (SFA) and monounsaturated fatty acids (MUFA) have differential acute effects on low-grade inflammation in REL compared to controls (CON). METHODS In randomized order, 17 REL and 17 CON ingested two fat-rich meals, with 72 energy percent from MUFA and 79 energy percent from mainly medium-chain SFA, respectively. Plasma high sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6), adiponectin, and leptin were measured at baseline, 15 min, 60 min, and 240 min postprandially. Muscle and adipose tissue biopsies were taken at baseline and 210 min after the test meal, and expression of selected genes was analyzed. RESULTS Plasma IL-6 increased (p < 0.001) without difference between REL and CON and between the meals, whereas plasma adiponectin and plasma hs-CRP were unchanged during the 240 min observation period. Plasma leptin decreased slightly in response to medium-chain SFA in both groups, and to MUFA in REL. Several genes were differentially regulated in muscle and adipose tissue of REL and CON. CONCLUSIONS MUFA and medium-chain SFA elicit similar postprandial circulating inflammatory responses in REL and CON. Medium-chain SFA seems more proinflammatory than MUFA, judged by the gene expression in muscle and adipose tissue of REL and CON.

Alcohol and postexercise metabolic responses in type 2 diabetes.

The objective was to investigate the impact of the combination of exercise and alcohol on the metabolic response in nonfasting and fasting type 2 diabetic subjects. In part 1, 12 untrained middle-aged type 2 diabetic subjects participated on 3 test days. On each day, they ingested a light meal (1,824 kJ) containing 48 energy percent (E%) carbohydrate, 38 E% fat, and 14 E% protein. The meal was followed by either (A) rest or (B) 30 minutes of exercise (40% of maximum O2 consumption [VO2max]) or (C) taken with alcohol (0.4 g/kg body weight) followed by 30 minutes of exercise (40% of VO2max). In part 2, 11 untrained middle-aged type 2 diabetic subjects participated on 4 test days without a meal. The subjects were either (A) resting, (B) drinking alcohol (0.4 g/kg body weight), (C) exercising 30 minutes (40% of VO2max), or (D) drinking alcohol (0.4 g/kg body weight) and exercising 30 minutes (40% of VO2max). On each test day, regular blood samples were drawn for 4 hours for analysis of glucose, insulin, lactate, triglycerides, nonesterified fatty acid (NEFA), and ethanol. Comparing exercise and rest following a light meal (part 1, no change (7%) occurred in the plasma glucose response area (642 +/- 119 v 724 +/- 109 mmol x L(-1) x 240 min, NS). However, it was significantly reduced (by 27%) in response to exercise and alcohol (509 +/- 98 v 724 +/- 109 mmol x L(-1) x 240 min; P = .03). Similar serum insulin response areas were obtained. After exercise and alcohol, plasma lactate increased compared with the resting state (2.2 +/- 0.2 v 1.6 +/- 0.1 mmol x L(-1), P = .004) and with exercise alone (2.2 +/- 0.2 v 1.8 +/- 0.2 mmol x L(-1), P = .04). Serum NEFAs were significantly reduced by exercise and alcohol compared with the resting state (0.50 +/- 0.04 v 0.65 +/- 0.06 mmol x L(-1), P = .008) and with exercise alone (0.50 +/- 0.04 v 0.61 +/- 0.05 mmol x L(-1), P = .02). Similar serum triglycerides were found. During the fasting state (part 2), similar plasma glucose response areas were obtained in the four situations. The insulin response area to exercise and alcohol increased significantly compared with the resting state (3,325 +/- 744 v 882 +/- 295 pmol x L(-1) x 240 min, P = .02) and with exercise alone (3,325 +/- 744 v 1,328 +/- 422 pmol x L(-1) x 240 min, P = .007). No difference was found compared with alcohol alone. Plasma lactate was higher after alcohol intake versus the resting state (1.9 +/- 0.1 v 1.3 +/- 0.1 mmol x L(-1), P = .003), as well as after exercise and alcohol (1.9 +/- 0.1 v 1.3 +/- 0.1 mmol x L(-1), P = .01). After exercise and alcohol serum NEFAs were significantly reduced compared with the resting state (0.43 +/- 0.02 v 0.64 +/- 0.02 mmol x L(-1), P < .001), alcohol alone (0.43 +/- 0.02 v 0.51 +/- 0.02 mmol x L(-1), P < .001), and exercise alone (0.43 +/- 0.02 v 0.64 +/- 0.02 mmol x L(-1), P < .001). Serum triglycerides were similar in the four situations. We conclude that moderate exercise with or without moderate alcohol intake does not cause acute hypoglycemia either after a light meal or in the fasting state in untrained overweight type 2 diabetic subjects.

Stevioside Counteracts Beta-Cell Lipotoxicity without Affecting Acetyl CoA Carboxylase

Chronic exposure to high levels of free fatty acids impairs beta-cell function (lipotoxicity). Then basal insulin secretion (BIS) is increased and glucose-stimulated insulin secretion (GSIS) is inhibited. Acetyl CoA carboxylase (ACC) acts as the sensor for insulin secretion in pancreatic beta-cells in response to glucose and other nutrients. Stevioside (SVS), a diterpene glycoside, has recently been shown to prevent glucotoxic effect by regulating ACC activity. The aim of this study was to investigate whether SVS can alleviate impaired beta-cell function by regulating ACC activity. We exposed isolated rat islets and the clonal beta-cell line, INS-1E, to palmitate concentrations of 1.0 or 0.6 mM, respectively, for a period of 24 h to 120 h. The results showed that lipotoxicity occurred in rat islets after 72 h exposure to 1.0 mM palmitate. The lipotoxicity was counteracted by 10(-6) M SVS (n = 8, p < 0.001). Similar results were obtained in INS-1E cells. Neither SVS nor palmitate had any effect on the gene expression of ACC, insulin 2, and glucose transporter 2 in INS-1E cells. In contrast, palmitate significantly increased the gene expression of carnitine palmitoyl transporter 1 (n = 6, p = 0.003). However, the addition of SVS to palmitate did not counteract this effect (n = 6, p = 1.0). During lipotoxicity, SVS did not alter levels of ACC protein, phosphorylated-ACC, ACC activity or glucose uptake. Our results showed that SVS counteracts the impaired insulin secretion during lipotoxicity in rat islets as well as in INS-1E cells without affecting ACC activity.

A Combination of Coffee Compounds Shows Insulin-Sensitizing and Hepatoprotective Effects in a Rat Model of Diet-Induced Metabolic Syndrome

Since coffee may help to prevent the development of metabolic syndrome (MetS), we aimed to evaluate the short- and long-term effects of a coffee-based supplement on different features of diet-induced MetS. In this study, 24 Sprague Dawley rats were divided into control or nutraceuticals groups to receive a high-fat/high-fructose diet with or without a mixture of caffeic acid (30 mg/day), trigonelline (20 mg/day), and cafestol (1 mg/day) for 12 weeks. An additional 11 rats were assigned to an acute crossover study. In the chronic experiment, nutraceuticals did not alter body weight or glycemic control, but improved fed hyperinsulinemia (mean difference = 30.80 mU/L, p = 0.044) and homeostatic model assessment-insulin resistance (HOMA-IR) (mean difference = 15.29, p = 0.033), and plasma adiponectin levels (mean difference = −0.99 µg/mL, p = 0.048). The impact of nutraceuticals on post-prandial glycemia tended to be more pronounced after acute administration than at the end of the chronic study. Circulating (mean difference = 4.75 U/L, p = 0.014) and intrahepatocellular alanine transaminase activity was assessed by hyperpolarized-13C nuclear magnetic resonance NMR spectroscopy and found to be reduced by coffee nutraceuticals at endpoint. There was also a tendency towards lower liver triglyceride content and histological steatosis score in the intervention group. In conclusion, a mixture of coffee nutraceuticals improved insulin sensitivity and exhibited hepatoprotective effects in a rat model of MetS. Higher dosages with or without caffeine deserve to be studied in the future.