Relation of Fetal Growth to Adult Muscle Mass and Glucose Tolerance

Recent studies show reduced fetal growth is associated with insulin resistance and a raised prevalence of glucose intolerance in adult life. Because early growth retardation in animal models leads to permanent changes in body composition and a reduction in the mass of muscle, a major insulin sensitive tissue, reduced adult muscle mass could explain the link between impaired fetal growth and glucose intolerance. To investigate this hypothesis, muscle mass has been determined in a group of men and women aged around 50 who were born in Preston, Lancashire and compared with their birthweight or body size at birth and their current insulin resistance and glucose tolerance. Subjects who had lower birthweights were shorter and lighter but their weight adjusted for height (BMI) was similar to that of other subjects. Much of the difference in weight was accounted for by a reduction in muscle mass. Muscle mass as estimated by the urinary creatinine excretion rose from 18.8 % of body weight in women who had birthweights of 2.5 kg or less to 24.7% of bodyweight in those with birthweights of 3.4 kg or more. Trends in men were similar. Regression analysis showed that adult muscle mass was predicted by low birthweight (p = 0.004), low placental weight (p = 0.02), and small head circumference (p = 0.02) but not, however, by thinness at birth, the birth measurement most predictive of insulin resistance. In addition there were no significant relationships between muscle mass and insulin resistance or glucose tolerance in either men or women. These results may be explained by the existence of two populations of babies both characterized by low birthweight. Babies who are symmetrically small at birth have reduced muscle mass in adult life. They do not, however, have increased insulin resistance or a tendency to develop glucose intolerance. Thin babies have a normal adult muscle mass; their tendency to develop insulin resistance or glucose intolerance is not explained by alterations in muscle mass.     

Postprandial hypertriglyceridemia and insulin resistance in normoglycemic first-degree relatives of patients with type 2 diabetes.

BACKGROUND: Impaired ability to eliminate lipids in the postprandial state is an atherogenic trait associated with insulin resistance. OBJECTIVE: To assess insulin sensitivity and postprandial triglyceride metabolism in prediabetic persons. DESIGN: Cross-sectional study. SETTING: Sahlgrenska University Hospital, G?teborg, Sweden. PARTICIPANTS: 13 healthy, normotriglyceridemic men with two first-degree relatives with type 2 diabetes and 13 carefully matched controls without known diabetes heredity. MEASUREMENTS: Oral glucose tolerance test, insulin sensitivity (euglycemic clamp technique), and fasting and postprandial triglyceride levels after a mixed meal. RESULTS: Relatives of persons with type 2 diabetes were insulin resistant but had normal glucose tolerance. They exhibited postprandial hypertriglyceridemia; the 6-hour triglyceride incremental area under the curve was 50% higher than that of the control group (P = 0.037). CONCLUSIONS: These healthy male first-degree relatives of patients with type 2 diabetes are insulin resistant and exhibit postprandial lipid intolerance despite having normal fasting triglyceride levels. These characteristics, which occur in the absence of glucose intolerance, are associated with an increased risk for macroangiopathy.     

A common apolipoprotein B signal peptide polymorphism modifies the relation between plasma non-esterified fatty acids and triglyceride concentration in men

Insulin and non-esterified fatty acids (NEFA) are important regulators of triglyceride metabolism. The relations between these compounds and the effect of a common 3 amino acid deletion in the apolipoprotein B (ApoB) signal peptide (SP) following an oral glucose challenge have been investigated. The frequency of the shorter SP-24 allele was 32% (95% C.I. 29.5-36.5) in 725 subjects undergoing an oral glucose tolerance test (OGTT). Fasting plasma triglyceride concentration was positively correlated with fasting plasma insulin concentration and negatively with the degree of plasma NEFA suppression following the glucose challenge. Linear regression analysis showed the relation between triglyceride concentration and NEFA suppression, but not the relation between triglyceride concentration and fasting insulin, to be altered by the SP polymorphism in men but not in women. The strength of the association was dependent on the number of SP-24 alleles, with SP-24 homozygotes showing the greatest dependence (men P=0.031, women P=0. 914). It was proposed that the complex regulation of very low density lipoprotein (VLDL) output by NEFA and by insulin may explain, at least in part, the conflicting reports concerning the presence of the ApoB SP polymorphism, fasting serum lipids and ischaemic heart disease (IHD).     

Glucose tolerance and resistance to insulin-stimulated glucose uptake in men aged 70 years in relation to size at birth

Summary Although several studies have shown that reduced size at birth predicts glucose intolerance and insulin resistance in adult life, the relation has been inconsistent and usually stronger for ponderal index than for birthweight. We examined glucose tolerance and insulin sensitivity (by the euglycaemic clamp method) in relation to size at birth in 709 men aged 69–73 years in Uppsala, Sweden. After adjusting for adult body mass index, prevalence of glucose intolerance (defined as diabetes or impaired glucose tolerance) was inversely related to birthweight. In men born at term, there was a positive monotonic relation of insulin sensitivity with birthweight, strongest in those who were overweight at age 70. This relation was reversed in men born before term (p = 0.005 for interaction between pre-term birth and birthweight effect). Glucose intolerance and insulin resistance showed inverted U-shaped relations with ponderal index, in contrast with the monotonic inverse relation seen in this cohort at earlier ages. This change in form of the relations was partly accounted for by selective loss to follow-up between ages 60 and 70 years. These results confirm that the association between reduced fetal growth and glucose intolerance is mediated through insulin resistance and depends upon an interaction with obesity in adult life. This relation is obscured when pre-term births are included. Failure to stratify by gestational age in previous studies could account for inconsistencies in the relations of insulin resistance and glucose intolerance to size at birth and for the detection of stronger associations with ponderal index than with birthweight. [Diabetologia (1998) 41: 1133–1138] Received: 17 March 1998 and in revised form: 25 May 1998     

Birth weight is nongenetically associated with glucose intolerance in elderly twins, independent of adult obesity

OBJECTIVES: Using a unique twin approach, we examined the extent to which birth weight is determined by genetic and nongenetic factors and whether associations between birth weight and measures of glucose metabolism are of genetic or nongenetic origin. SETTING/SUBJECTS: An oral glucose tolerance test (OGTT) was performed in a population-based cohort of twins including 138 same-sex monozygotic (MZ) and 214 dizygotic (DZ) twin pairs aged 55-73 years whose birth weight was known. Heritability of birth weight was determined and regression analyses with intra-twin pair differences of birth weight and measures of glucose metabolism, with and without adjustment for adult obesity, were performed. RESULTS: The heritability of birth weight was estimated to be 38%. We demonstrated significant nongenetic associations between birth weight and measures of glucose homeostasis in MZ twins, with a reduction in fasting plasma glucose, 120 min post-OGTT plasma glucose, fasting plasma insulin and HOMA-IR index of 15.7%, 25.5%, 26.4% and 37.2%, respectively, for every 1 kg increase in birth weight. The nongenetic negative associations between birth weight and measures of glucose intolerance were independent of adult obesity, whereas the nongenetic association between birth weight and insulin resistance persisted, although not as strongly, after adjusting for current body size. CONCLUSIONS: We demonstrated a genetic component to birth weight in elderly twins. When adjusting for this influence, we found a nongenetic negative association between birth weight and glucose tolerance as well as insulin resistance that was partially independent of adult obesity. This implies that the foetal environment influences glucose homeostasis in elderly twins.     

Fetal growth and insulin secretion in adult life

Summary Recent studies suggest that NIDDM is linked with reduced fetal and infant growth. Observations on malnourished infants and studies of experimental animals exposed to protein energy or protein deficiency in fetal or early neonatal life suggest that the basis of this link could lie in the detrimental effects of poor early nutrition on the development of the beta cells of the islets of Langerhans. To test this hypothesis we have measured insulin secretion following an IVGTT in a sample of 82 normoglycaemic and 23 glucose intolerant subjects who were born in Preston, England, and whose birthweight and body size had been recorded at birth. The subjects with impaired glucose tolerance had lower first phase insulin secretion than the normoglycaemic subjects (mean plasma insulin concentrations 3 min after intravenous glucose 416 vs 564 pmol/l, p=0.04). Insulin secretion was higher in men than women (601 vs 457 pmol/l, P=0.02) and correlated with fasting insulin level (p=0.04). However, there was no relationship between insulin secretion and the measurements of prenatal growth in either the normoglycaemic or glucose intolerant subjects. These results argue against a major role for defective insulin secretion as a cause of glucose intolerance in adults who were growth retarded in pre-natal life.Abbreviations NIDDM Non-insulin-dependent diabetes - OGTT oral glucose tolerance test - IVGTT intravenous glucose tolerance test     

Is an exaggerated postprandial triglyceride response associated with the component features of the insulin resistance syndrome?

To investigate whether individual component features of the insulin resistance syndrome were associated with the postprandial triglyceride response, 57 healthy Caucasian men between 57 and 70 years of age underwent a fat tolerance test lasting 8 h. Fasting triglyceride concentrations were associated with the total unfractionated postprandial triglyceride response (r_s= 0.54, p<0.001) and the triglyceride-rich lipoprotein (TGRLP) fraction (d<1.006) at 8 h was associated with the maximum non-esterified fatty acid concentration (NEFA) (r_s = 0.33 p = 0.01). Measures of obesity (BMI and WHR) were not associated with the postprandial triglyceride response but were inversely related to NEFA suppression (NEFA nadir and BMI, r_s = 0.31, p = 0.02; and NEFA nadir and WHR, r_s = 0.36, p = 0.006). Other component features of the IRS, including glucose tolerance and two proxy measures of insulin resistance (fasting insulin concentration and HOMA measurement) were not associated with the postprandial triglyceride response despite being strongly associated with fasting triglyceride concentration. Current smoking habit, chronic alcohol consumption and birth weight were also not associated with an altered postprandial triglyceride response. In conclusion these results show that although component features of the IRS were associated with increased fasting triglyceride concentrations many of these features, including two proxy measures of insulin sensitivity were not associated with an exaggerated postprandial triglyceride response. © 1997 John Wiley & Sons, Ltd.     

Hypertriglyceridaemia in subjects with normal and abnormal glucose tolerance: relative contributions of insulin secretion,insulin resistance and suppression of plasma non-esterified fatty acids

Summary Although plasma insulin and triglyceride concentrations are positively correlated in many studies, the relationships between insulin resistance, insulin secretion and hypertriglyceridaemia remain unclear. To study these associations, subjects between the ages of 40 and 64 were randomly selected from a general practice register and invited to attend for a standard oral glucose tolerance test for measurement of insulin, triglyceride and non-esterified fatty acid concentrations. The study comprised 1122 subjects who were not previously known to have diabetes and who completed the test. Using the World Health Organisation criteria, 51 subjects were classified to have non-insulin-dependent diabetes mellitus, 188 had impaired glucose tolerance and 883 subjects had normal glucose tolerance. Triglyceride concentrations in subjects with glucose intolerance were elevated compared to those in control subjects, even after adjustment for age, obesity and gender (p<0.001 for subjects with diabetes and p<0.01 for those with impaired glucose tolerance compared to normal subjects). In separate multiple regression analyses for males and females, the most important determinants of the plasma triglyceride concentration were the area under the non-esterified fatty acid suppression curve (p<0.001 in both genders) and the waist-hip ratio (p<0.001 for men and <0.01 for women). The fasting insulin concentration was independently associated with triglyceride concentration in women only (p<0.01). The most important determinant of the area under the non-esterified fatty acid suppression curve in men was the 30-min insulin increment, a measure of insulin secretion, (p<0.001) whereas for women age (p<0.001) and the body mass index (p<0.01) were the most important.Abbreviations NIDDM non-insulin-dependent diabetes mellitus - IGT impaired glucose tolerance - NEFA non-esterified fatty acid     

Decreased non-esterified fatty acid suppression and features of the insulin resistance syndrome occur in a sub-group of individuals with normal glucose tolerance

Summary To investigate causes of increased triglyceride concentrations in subjects with normal glucose tolerance (determined by oral glucose tolerance testing using World Health Organization criteria) 883 healthy subjects (389 men and 494 women) between 40 and 65 years of age were studied. Subjects were divided by gender into four groups according to 120-min glucose concentrations. Individuals in the highest quartile of glucose concentration had the highest mean triglyceride concentrations (p<0.0001) and highest mean non-esterified fatty acid (NEFA) concentrations (p<0.0001). There was also a clustering of cardiovascular risk factors normally associated with the insulin resistance syndrome in subjects in this group. Regression analysis showed that the most important determinants of triglyceride levels were smoking (men p=0.001, women p=0.005), waist:hip ratio (men p=0.01, women p<0.001) and NEFA suppression (men p=0.02, women p=0.005). NEFAs suppressed 16.7% in women compared to 2.4% in men during the first 30 min of the oral glucose tolerance test (p<0.001). These results show that a clustering of cardiovascular risk factors associated with decreased NEFA suppression occurs in a sub-group of subjects with normal glucose tolerance and that the pattern of NEFA suppression differs between men and women.Abbreviations NEFA Non-esterified fatty acids - IHD ischaemic heart disease - HDL high density lipoprotein - IRS insulin resistance syndrome - VLDL very low density lipoprotein - OGTT oral glucose tolerance test - NIDDM non-insulin-dependent diabetes mellitus - WHR waist-hip ratio     

Adipose triglyceride lipase-null mice are resistant to high-fat diet-induced insulin resistance despite reduced energy expenditure and ectopic lipid accumulation

Adipose triglyceride lipase (ATGL) null (-/-) mice store vast amounts of triacylglycerol in key glucoregulatory tissues yet exhibit enhanced insulin sensitivity and glucose tolerance. The mechanisms underpinning these divergent observations are unknown but may relate to the reduced availability of circulating fatty acids. The aim of this study was to determine whether the enhancements in insulin stimulated glucose metabolism in ATGL-/- mice persist when challenged with a high-fat diet. ATGL-/- mice fed a low-fat diet exhibit improved whole-body insulin sensitivity and glucose tolerance compared with wild-type mice. Wild-type mice became hyperlipidemic and insulin-resistant when challenged with a high-fat diet (HFD, 60% fat) for 4 wk. ATGL-/- mice fed a HFD had elevated circulating fatty acids but had reduced fasting glycemia compared to pre-high-fat diet levels and were refractory to glucose intolerance and insulin resistance. This protection from high-fat diet-induced metabolic perturbations was associated with a preference for fatty acid utilization but reduced energy expenditure and no change in markers of mitochondrial capacity or density. The protection from high-fat diet-induced insulin resistance in ATGL-/- mice was due to increased cardiac and liver insulin-stimulated glucose clearance despite increased lipid content in these tissues. Additionally, there was no difference in skeletal muscle insulin-stimulated glucose disposal, but there was a reduction observed in brown adipose tissue. Overall, these results show that ATGL-/- mice are protected from HFD-induced insulin resistance and reveal a tissue specific disparity between lipid accumulation and insulin sensitivity.     

Coronary artery disease risk predicted by insulin resistance, plasma lipids, and hypertension in people without diabetes

BACKGROUND: It has been shown that insulin resistance syndrome, including glucose intolerance, dyslipidemia, and hypertension, is frequently associated with coronary artery disease (CAD). However, their relative contributions and predictive power in the development of CAD are still unclear, particularly in persons without diabetes. METHOD: We examined these risk factors between 96 patients without diabetes but with angiographically documented CAD and 96 age-, sex-, and body mass index-matched healthy control subjects. Fasting plasma lipoprotein, glucose, and insulin concentrations in response to a 75-g oral glucose tolerance test were determined, and insulin sensitivity was measured by the insulin suppression test. RESULTS: Patients with CAD had significantly higher values of fasting glucose, glucose and insulin responses to oral glucose tolerance test, total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglyceride and decreased high-density lipoprotein (HDL) cholesterol concentrations compared with those of healthy people (P < 0.02-0.001). Although the steady-state plasma insulin values were similar in both groups, the steady-state plasma glucose (SSPG) concentrations were significantly higher in patients with CAD (12.2+/-0.4 versus 8.1+/-0.4 mmol/L, P < 0.001) compared with healthy subjects. When HDL < 0.9 mmol/L, LDL cholesterol > or = 4.1 mmol/L, triglyceride > or = 2.3 mmol/L, SSPG > or = 10.5 mmol/L, and presence of hypertension were defined as separate risk factors for CAD, significantly higher odds-ratio values were observed in patients with CAD compared with healthy people. From logistic multiple regression analysis, SSPG was the strongest risk, followed by lowered HDL cholesterol, elevated triglyceride and LDL cholesterol, and hypertension, to predict CAD. These 5 factors accounted for 36% of total risk for development of CAD in persons without diabetes. CONCLUSIONS: Patients without diabetes with CAD have abnormal glucose metabolism, hyperinsulinemia, and insulin resistance. Degree of insulin resistance (SSPG values), plasma lipid values, and history of hypertension together accounted for one third of all risk for CAD, although degree of insulin resistance was the strongest risk factor.     

Relationships between insulin secretion, insulin metabolism and insulin resistance in mild glucose intolerance

The aim of this study was to evaluate whether the correlation between insulin resistance and peripheral hyperinsulinaemia existing in mild glucose intolerance corresponds to a relationship between insulin resistance and insulin overproduction by the pancreas. In addition, the possibility that insulin resistance is related to insulin metabolism was examined. Twenty five subjects with fasting normoglycaemia and an abnormal glucose response to the oral glucose tolerance test (OGTT) were studied. Insulin secretion by the pancreas was estimated by means of fasting C-peptide levels in peripheral blood. Insulin resistance was estimated by the rate of glucose disappearance from plasma after i.v. insulin injection. Insulin metabolism was estimated indirectly by the C-peptide: insulin molar ratio. A negative correlation was found between the glucose disappearance rate from plasma after i.v. insulin injection and fasting insulin levels (r = -0.677, p less than 0.001), but not fasting C-peptide concentrations (r = -0.164, p = NS). Glucose disappearance rate from plasma correlated positively with the C-peptide: insulin molar ratio (r = 0.626, p less than 0.001). These results suggest that in mild glucose intolerance insulin resistance and insulin secretion by the pancreas are not related phenomena, and that the defect responsible for insulin resistance might also be implicated in the impaired insulin metabolism.     

Effect of liraglutide on estimates of lipolysis and lipid oxidation in obese patients with stable coronary artery disease and newly diagnosed type 2 diabetes: A randomized trial

Elevated levels of non-esterified fatty acids (NEFA) play a role in insulin resistance, impaired beta-cell function and they are a denominator of the abnormal atherogenic lipid profile that characterizes obese patients with type 2 diabetes (T2DM). We hypothesized that the GLP-1 receptor agonist liraglutide, in combination with metformin, would reduce lipolysis. In a randomized, double-blind, placebo-controlled, cross-over trial, 41 T2DM patients with coronary artery disease were randomized and treated with liraglutide-metformin vs placebo-metformin during 12- + 12-week periods with a wash-out period of at least 2 weeks before and between the intervention periods. NEFA kinetics were estimated using the Boston Minimal Model of NEFA metabolism, with plasma NEFA and glucose levels measured during a standard 180-minute frequently sampled intravenous glucose tolerance test. Liraglutide-metformin reduced estimates of lipolysis. Furthermore, placebo-metformin increased estimates of lipid oxidation, while treatment with liraglutide eliminated this effect. We conclude that liraglutide exerts a clinically relevant reduction in estimates of lipolysis and lipid oxidation which is explained, in part, by improved insulin secretion, as revealed by an intravenous glucose tolerance test.     

Rosiglitazone treatment of patients with extreme insulin resistance and diabetes mellitus due to insulin receptor mutations has no effects on glucose and lipid metabolism

BACKGROUND: Rosiglitazone, a thiazolidinedione (TZD), increases insulin sensitivity by reducing levels of plasma NEFA, triglycerides (TG), glucose and serum insulin. Rosiglitazone treatment decreases insulin resistance in type 2 diabetic patients, but no data exist concerning rosiglitazone treatment of patients with syndromes of extreme insulin resistance. OBJECTIVES: To evaluate whether hyperglycaemia in two lean patients with primary severe insulin resistance due to insulin receptor (IR) mutations and diabetes mellitus could be reduced by supplement of rosiglitazone for 180 days and secondary, to evaluate the effects on plasma NEFA, TG, Apo B, PAI-1 and serum insulin. SUBJECTS: Both patients (brothers) have known mutations in the IR gene localized to the tyrosine kinase domain and a deletion of exon 17 in part of their IR mRNA. Prior to the study the HbA1c values were higher than 10% in both patients for more than 12 months during treatment with insulin and metformin. RESULTS: After 180 days of rosiglitazone supplement (8 mg day(-1)), no changes were observed in fasting plasma glucose and HbA1c. Incremental plasma glucose areas under the curves during a 75-g oral glucose tolerance test (OGTT) were unchanged. Likewise, no improvements were seen in either first or second phase insulin secretion during a 0.3 g kg(-1) intravenous glucose tolerance test (IVGTT). Fasting plasma VLDL and HDL cholesterol, TG and Apo B levels were unchanged, whereas a small increase was seen in total and LDL cholesterol levels. Fasting plasma NEFA increased by 51% in KC after 90 days of treatment, and after 180 days plasma NEFA was still 26% higher, when compared with pretreatment levels. In BC an initial 16% decrease was seen in plasma NEFA after 90 days of treatment. Plasma NEFA was increased 14% after 180 days of treatment, when compared with pretreatment levels, but 35% when compared with day 90. Plasma PAI-1 decreased in both patients after 45 and 90 days of treatment but the decrease was only maintained in KC (47%). CONCLUSIONS: Rosiglitazone treatment, in combination with insulin and metformin, of patients with severe primary insulin resistance due to IR mutations and diabetes mellitus, had no impact on the measured estimates of glucose and lipid metabolism. These findings may suggest that the effect of rosiglitazone on glucose and lipid metabolism are dependent on the presence of intact IR protein.     

Insulin resistance in porphyria cutanea tarda

It has been reported that patients with porphyria cutanea tarda (PCT) develop carbohydrate (CHO) intolerance and manifest diabetes melitus (DM) more frequently than the normal population. In order to verify whether this is due to insulin resistance we studied 5 patients with PCT and 5 normal subjects matched for age, sex and weight. In all the patients an evaluation consisted of the glycemic curve and insulin response to an iv glucose tolerance test (IVGTT: 0.33 g/kg) as well as of an evaluation of the circulating monocyte insulin receptors. Blood samples were drawn in the basal state to measure plasma levels of NEFA, glycerol, and intermediate metabolites. The patients with PCT showed normal glucose tolerance which was obtained, however, at the expense of the elevated insulin levels: therefore a condition of insulin resistance was demonstrated in these subjects. An involvement of the lipid metabolism, observed by the raised levels of plasma NEFA and glycerol, was also evident. The insulin binding to circulating monocytes was reduced but not enough to justify the degree of insulin resistance observed. Therefore, it could be hypothesized, in agreement with similar studies, that a postreceptor defect is responsible for the insulin-resistance observed in patients with PCT and that the reduction of insulin receptors is determined by the down regulation in response to elevated insulinemic levels. An alteration of the porphyrin metabolism might be responsible for this disorder.     

Thinness at birth and insulin resistance in adult life

Summary Type 2 (non-insulin-dependent) diabetes mellitus may originate through impaired development in fetal life. Both insulin deficiency and resistance to the action of insulin are thought to be important in its pathogenesis. Although there is evidence that impaired fetal development may result in insulin deficiency, it is not known whether insulin resistance could also be a consequence of reduced early growth. Insulin resistance was therefore measured in 81 normoglycaemic subjects, and 22 subjects with impaired glucose tolerance, who were born in Preston, UK, between 1935 and 1943. Their birth measurements had been recorded in detail. Insulin resistance was measured by the insulin tolerance test which uses the rate of fall in blood glucose concentrations after intravenous injection of insulin as an index of insulin resistance. Men and women who were thin at birth, as measured by a low ponderal index, were more insulin resistant. The association was statistically significant (p =0.01) and independent of duration of gestation, adult body mass index and waist to hip ratio and of confounding variables including social class at birth or currently. Thinness at birth and in adult life has opposing effects such that resistance fell with increasing ponderal index at birth but rose with increasing adult body mass index. It is concluded that insulin resistance is associated with impaired development in fetal life. [Diabetologia (1994) 37: 150–154] Received: 24 May 1993 and in revised form: 6 August 1993     

Fat storage is partially dependent on vagal activity and insulin secretion of hypothalamic obese rat

Hypothalamic MSG-obese rats show hyperinsulinemia and tissue insulin resistance, and they display intense parasympathetic activity. Current analysis investigates whether early subdiaphragmatic vagotomy prevents tissue insulin sensitivity impairment in adult obese MSG-rats. Hypothalamic obesity was induced by MSG (4 mg/g BW), daily, from birth up to 5 days. Control animals receiving saline solution. On the 30th day rats underwent bilateral subdiaphragmatic vagotomy or sham surgery. An intravenous glucose tolerance test (ivGTT) was performed when rats turned 90 days old. Total white fat tissue (WAT) from rat carcass was extracted and isolated; the interscapular brown fat tissue (IBAT) was weighed. Rather than blocking obesity, vagotomy reduced WAT and IBAT in MSG-obese rats when the latter were compared to sham MSG-rats. High blood fasting insulin and normal glucose levels were also observed in MSG-obese rats. Although glucose intolerance, high insulin secretion, and significant insulin resistance were recorded, vagotomy improved fasting insulinemia, glucose tolerance and insulin tissue sensitivity in MSG-obese rats. Results suggest that increased fat accumulation is caused, at least in part, by high blood insulin concentration, and enhanced parasympathetic activity on MSG-obese rats.     

Impaired glucose tolerance and fasting hyperglycaemia have different characteristics.

AIMS: Use of the oral glucose tolerance test (OGTT) to define glucose intolerance in the general population may bias towards selection of those with insulin resistance. Beta cell function and insulin resistance markers were analysed in four groups: controls (n = 101); fasting hyperglycaemia (FH, n 45); impaired glucose tolerance; (IGT, n = 16) and those with features of both FH and IGT ('Both', n = 30). METHODS: Subjects underwent an OGTT. Plasma glucose, fasting lipid profiles, fasting, 30 and 120 min insulin were measured and beta cell function (% B) and insulin sensitivity (% S) assessed by homeostatic model assessment (HOMA) RESULTS: The FH group compared to controls had a significantly lower % B. The IGT group compared to controls had features of insulin resistance (higher body mass index (BMI), systolic blood pressure and 2 h insulin concentration). Subjects with 'both' IGT and FH had features of insulin resistance (higher BMI, systolic and diastolic blood pressure and triglyceride concentration) as well as beta cell dysfunction with a lower % B and 30 min insulin-glucose ratio compared to controls. There was a preponderance of males in this group. In all, 192 subjects' 30-min insulin concentration and incremental insulin response showed only a significantly negative correlation with fasting glucose concentration. In a linear regression analysis, a low 30-min insulin-glucose ratio was only a significant factor in the fasting glucose model. Thus, higher fasting glucose concentrations appear to be associated with beta cell dysfunction. However, HbA1 only showed a significant correlation with 120-min glucose, not fasting glucose concentration. CONCLUSIONS: In those with milder degrees of glucose intolerance, FH is associated with beta cell dysfunction and those with IGT and a relatively 'normal' fasting glucose have features of the insulin resistance syndrome.     

Treatment of type 2 (non-insulin-dependent) diabetic patients with diet alone

Summary The effects of 3 months' diet therapy on glucose tolerance, plasma insulin response to oral glucose, fasting lipid levels and body weight were measured in 182 Type 2 (non-insulin-dependent) diabetic outpatients with fasting hyperglycaemia before treatment. Overall, there was a 25% improvement in glucose tolerance, a 58% increase in plasma insulin response during the glucose tolerance test, a 13.6% fall in fasting plasma triglyceride levels with no change in fasting cholesterol levels and a 5.1% fall in body weight. Of the 182 patients, 20% achieved normal glucose tolerance on diet alone for 3 months. These were mainly men of average age 63 years, who were 20% above their ideal body weight, and had milder glucose intolerance and higher residual insulin response to glucose before treatment than the 16% of patients who remained poorly controlled. These latter patients were mainly older women, 9% above their ideal body weight and with more marked glucose intolerance and less insulin response to glucose. These results demonstrate the practical limitations of this type of anti-diabetic therapy, particularly if normal glucose tolerance is a desired therapeutic aim.     

Glucose intolerance induced by a high-fat/low-carbohydrate diet in rats effects of nonesterified fatty acids

We examined the time course of effects of a high-fat/low-carbohydrate (HF/LC) diet on the impairment of glucose tolerance in rats, clarified whether insulin secretion and sensitivity were impaired by the HF/LC diet, and investigated the relationship between the increased nonesterified fatty acids (NEFA) after HF/LC diet feeding and insulin secretion and sensitivity. We found that glucose tolerance and the postglucose-loading insulin secretion were impaired after 3 and 7 d on the HF/LC diet. The glucose intolerance was accompanied by a rise in the fasting plasma NEFA level. When stimulated with 15 mmol/L of glucose, the insulin secretion was impaired in pancreatic islets from rats fed the HF/LC diet. Rats fed the HF/LC diet showed insulin resistance in vivo. The glucose-stimulated insulin secretion was inhibited in the islets following 24-h culture with palmitic acid. The 24-h infusion of palmitic acid decreased whole-body insulin sensitivity. In summary, at least 3 d on a HF/LC diet is needed to induce glucose intolerance in rats, and the impairment may be induced by decreased insulin secretion and sensitivity, which is related to the increase in the plasma NEFA level.