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Biomedical subjects

A B Jenkins

Publications and source records attributed to A B Jenkins.

At least 37 records · Page 2Linked to original sources
PubMed1997

Fatty acids, triglycerides and syndromes of insulin resistance.

Muscle plays a major role in insulin-stimulated glucose disposal. There is now a range of evidence in humans and experimental animals demonstrating strong relationships between the fatty acid composition of structural membrane lipids and insulin action. The in vivo work is correlative but the in vitro studies suggest a causal relationship exists. Good insulin action is associated with an increased proportion of n-3 fatty acids, low saturates, a low n-6/n-3 ratio and possibly increased monounsaturates. What is reassuring is that there is a pleasing symmetry with the fatty acid pattern that might lead to decreased thrombosis. There is little argument about saturated fats with a reduction having a range of beneficial effects. However, the n-3 fatty acids might also be a key to amelioration of both insulin resistance and thrombosis. The sites of action of n-3s are multiple: decreased triglyceride and VLDL production; inhibition of thromboxane A2 production, increased thromboxane A3 and decreased platelet aggregation; reduction of triglyceride and VLDL concentration; improved blood rheology and membrane transport; action on the endothelium and proliferation of the intimal cells, and improvement of vascular tone. The data here are now strong and reasonably consistent. Similarly, after initial controversy, the evidence for n-3s playing a beneficial role in insulin action is now accumulating. The n-6 PUFAs are a bit of a worry: while arachidonic acid levels in muscle phospholipid has linked positively to insulin action in our studies, linoleic is negative. Linoleic acid, in high amounts, is known to inhibit the delta6 fatty acid desaturase enzyme and with the competition between n-6 and n-3 fatty acids for the enzymes of desaturation and elongation it does focus on a high n-6/n-3 ratio as a critical factor in both insulin resistance and atherosclerosis.

Animals↗
PubMed1997

Skeletal muscle triglyceride levels are inversely related to insulin action.

In animal studies, increased amounts of triglyceride associated with skeletal muscle (mTG) correlate with reduced skeletal muscle and whole body insulin action. The aim of this study was to test this relationship in humans. Subjects were 38 nondiabetic male Pima Indians (mean age 28 +/- 1 years). Insulin sensitivity at physiological (M) and supraphysiological (MZ) insulin levels was assessed by the euglycemic clamp. Lipid and carbohydrate oxidation were determined by indirect calorimetry before and during insulin administration. mTG was determined in vastus lateralis muscles obtained by percutaneous biopsy. Percentage of body fat (mean 29 +/- 1%, range 14-44%) was measured by underwater weighing. In simple regressions, negative relationships were found between mTG (mean 5.4 +/- 0.3 micromol/g, range 1.3-1.9 micromol/g) and log10M (r = -0.53, P < or = 0.001), MZ (r = -0.44, P = 0.006), and nonoxidative glucose disposal (r = -0.48 and -0.47 at physiological and supraphysiological insulin levels, respectively, both P = 0.005) but not glucose or lipid oxidation. mTG was not related to any measure of adiposity. In multiple regressions, measures of insulin resistance (log10M, MZ, log10[fasting insulin]) were significantly related to mTG independent of all measures of obesity (percentage of body fat, BMI, waist-to-thigh ratio). In turn, all measures of obesity were related to the insulin resistance measures independent of mTG. The obesity measures and mTG accounted for similar proportions of the variance in insulin resistance in these relationships. The results suggest that in this human population, as in animal models, skeletal muscle insulin sensitivity is strongly influenced by local supplies of triglycerides, as well as by remote depots and circulating lipids. The mechanism(s) underlying the relationship between mTG and insulin action on skeletal muscle glycogen synthesis may be central to an understanding of insulin resistance.

Adult↗
PubMed1996

Skeletal muscle membrane lipids and insulin resistance.

Skeletal muscle plays a major role in insulin-stimulated glucose disposal. This paper reviews the range of evidence in humans and experimental animals demonstrating close associations between insulin action and two major aspects of muscle morphology: fatty acid composition of the major structural lipid (phospholipid) in muscle cell membranes and relative proportions of major muscle fiber types. Work in vitro and in vivo in both rats and humans has shown that incorporation of more unsaturated fatty acids into muscle membrane phospholipid is associated with improved insulin action. As the corollary, a higher proportion of saturated fats is linked to impairment of insulin action (insulin resistance). Studies in vitro suggest a causal relationship. Among polyunsaturated fatty acids (PUFA) there is some, but not conclusive, evidence that omega-3 (n-3) PUFA may play a particular role in improving insulin action; certainly a high n-6/n-3 ratio appears deleterious. In relation to fiber type, the more highly oxidative, insulin-sensitive type 1 and type 2a fibers have a higher percentage of unsaturated fatty acids, particularly n-3, in their membrane phospholipid, compared to the insulin-resistant, glycolytic, type 2b fibers. These variables, however, can be separated and may act in synergy to modulate insulin action. It remains to establish whether lifestyle (e.g., dietary fatty acid profile and physical activity), genetic predisposition, or a combination are the prime determinants of muscle morphology (particularly membrane lipid profile) and hence insulin action.

Animals↗
PubMed1996

Interrelationships between muscle morphology, insulin action, and adiposity.

There is evidence that insulin resistance and obesity are associated with relative increases in the proportion of glycolytic type IIb muscle fibers and decreases in the proportion of oxidative type I fibers. Futhermore, insulin resistance and obesity are associated with the fatty acid (FA) profile of structural membrane lipids. The present study was undertaken to define interrelationships between muscle fiber type and oxidative capacity, muscle membrane FA composition, and insulin action and obesity. Muscle morphology, insulin action, and body fat content were measured in 48 male nondiabetic Pima Indians. Percent body fat (pFAT, determined by hydrodensitometry) correlated negatively with percentage of type I fibers (r = -0.44, P = 0.002) and positively with percentage of type IIb fibers (r = 0.40, P = 0.005). Consistent with this finding, pFAT was also significantly related to oxidative capacity of muscle, as assessed by NADH staining (r = -0.47, P = 0.0007) and citrate synthase (CS) activity (r = -0.43, P = 0.008). Insulin action was correlated with oxidative capacity (CS; r = 0.41, P = 0.01) and weakly correlated with percentage of type IIb fibers (r = -0.29, P = 0.05). In addition, relationships were shown between muscle fiber type and FA composition (e.g., percentage of type I fibers related to n-3 FA; r = 0.37, P = 0.01). Thus leaness and insulin sensitivity are associated with increased oxidative capacity and unsaturation of membranes in skeletal muscle. Present studies support the hypothesis that muscle oxidative capacity and fiber type may play a genetically determined or an environmentally modified role in development of obesity and insulin resistance.

Adipose Tissue↗
PubMed1996

Growth hormone-induced insulin resistance and its relationship to lipid availability in the rat.

The role of increased lipid availability in the generation of insulin resistance by growth hormone has not been established. We investigated this in rats infused with saline (controls) or human growth hormone (hGH) (500 micrograms x kg-1 x 24 h-1) for 5 h or 3 days. hGH infusion increased basal plasma insulin at 5 h (335 +/- 33 vs. 197 +/- 15 [controls]; P < 0.005) and at 3 days (396 +/- 34 vs. 218 +/- 14 pmol/l; P < 0.0001). Plasma nonesterified fatty acid (0.26 +/- 0.01 vs. 0.21 +/- 0.01 [controls] g/l) and liver long-chain acyl-CoA (21.2 +/- 1.9 vs. 14.1 +/- 1.1 [controls] nmol/g wet wt) were elevated at 5 h (P < 0.01 for both) but were below control levels after 3 days of hGH infusion (P < 0.01 for both); indirect calorimetry after 3 days demonstrated decreased lipid oxidation. Clamp studies showed similar degrees of peripheral insulin resistance at 5-h and 3-day hGH infusion (glucose disposal reduced by 25% versus controls). Insulin-stimulated glucose metabolic index (Rg') in red gastrocnemius muscle (red muscle) was reduced (P < 0.05 and P < 0.01) at 5 h and 3 days of hGH infusion, respectively (e.g., 5 h, 10.0 +/- 1.8 vs. 24.1 +/- 4.4 [controls] micromol x 100 g-1 x min-1), whereas insulin-mediated muscle glycogen synthesis was reduced (P < 0.03) only in rats infused with hGH for 3 days. We conclude that in the rat, hGH rapidly induces persistent peripheral insulin resistance and basal hyperinsulinemia. However, the transient nature of increased lipid mobilization suggests that it is not an important factor in the manifestation of muscle insulin resistance during prolonged hGH elevation. The persistent insulin resistance is not associated with increased lipid oxidation but is associated with hyperinsulinemia and reduced insulin-mediated muscle glycogen synthesis.

Adipose Tissue↗
PubMed1996

Abdominal fat and insulin resistance in normal and overweight women: Direct measurements reveal a strong relationship in subjects at both low and high risk of NIDDM.

Insulin resistance appears to be central to obesity, NIDDM, hyperlipidemia, and cardiovascular disease. While obese women with abdominal (android) fat distribution are more insulin resistant than those with peripheral (gynecoid) obesity, in nonobese women, the relationship between abdominal fat and insulin resistance is unknown. By measuring regional adiposity with dual-energy X-ray absorptiometry and insulin sensitivity by euglycemic-hyperinsulinemic clamp in 22 healthy women, with a mean +/- SE body BMI of 26.7 +/- 0.9 kg/m2 and differing risk factors for NIDDM, we found a strong negative relationship between central abdominal (intra-abdominal plus abdominal subcutaneous) fat and whole-body insulin sensitivity (r = -0.89, P < 0.0001) and nonoxidative glucose disposal (r = -0.77, P < 0.001), independent of total adiposity, family history of NIDDM, and past gestational diabetes. There was a large variation in insulin sensitivity, with a similar variation in central fat, even in those whose BMI was <25 kg/m2. Abdominal fat had a significantly stronger relationship with insulin sensitivity than peripheral nonabdominal fat (r2 = 0.79 vs. 0.44), and higher levels were associated with increased fasting nonesterified fatty acids, lipid oxidation, and hepatic glucose output. Because 79% of the variance in insulin sensitivity in this heterogeneous population was accounted for by central fat, abdominal adiposity appears to be a strong marker and may be a major determinant of insulin resistance in women.

Abdomen↗
PubMed1996

Glycemic responses to exercise in IDDM after simple and complex carbohydrate supplementation.

OBJECTIVE: Subjects with IDDM should take carbohydrate before exercise to avoid hypoglycemia. However, there is little information on the glycemic effect of recommended supplementation. This study is aimed to determine the glycemic effects of oral glucose or bread (30 g carbohydrate) before 45 min of moderate exercise. RESEARCH DESIGN AND METHODS: Nine subjects with uncomplicated IDDM did 45 min of bicycle ergometer exercise at 60% VO2max in the morning before insulin injection on three occasions: 1) with no carbohydrate supplement, 2) with 30 g glucose in water at -5 min, and 3) with 30 g carbohydrate as white bread with water at -20 min. The glycemic responses were determined. The glycemic responses to glucose and bread were also determined without exercise in six subjects. RESULTS: Without carbohydrate, exercise caused a small fall (-1.2 +/- 0.6 mmol/l, mean +/- SE) in plasma glucose (PG). With either glucose or bread, PG rose (the change in plasma glucose relative to basal [delta PG] = 5.1 +/- 0.8 and 2.6 +/- 0.8, respectively). The rise was greater (P < 0.01) without exercise (delta PG = 6.9 +/- 0.7 and 4.5 +/- 0.7, respectively). During exercise, glucose increased PG levels more than bread increased glucose levels P < 0.05). CONCLUSIONS: Before morning insulin injection, the fall in PG during moderate exercise in IDDM subjects is generally small or absent. The glycemic effects of complex carbohydrate are slightly less than glucose before exercise. Under these circumstances, the usually recommended amount of carbohydrate tends to cause an unwanted elevation of PG; thus, IDDM subjects should anticipate reducing or even omitting carbohydrate supplementation after monitoring their individual glycemic response.

Adolescent↗
PubMed1995

Importance of early insulin levels on prandial glycaemic responses and thermogenesis in non-insulin-dependent diabetes mellitus.

To examine the effect of different profiles of insulin administration on glycaemia and thermogenesis, we studied 10 subjects with mild non-insulin-dependent diabetes mellitus on four occasions after a standard mixed meal: (1) with no supplementary insulin (control), (2) with intravenous insulin (1.8U over 15 min = short), (3) as for short but extended over 30 min to simulate the normal initial rise in portal vein insulin levels (medium), (4) as for medium with additional insulin to normalize the profile from 30-60 min (3.6U over 60 min, long). All studies in which supplemental insulin was administered lowered the integrated glucose response above baseline versus the control study (short 76%, medium 71%, and long 56% of control, p = 0.003). The insulin infusions also increased the non-protein respiratory quotient in the first hour following the meal (0.82 +/- 0.01 (control) vs 0.87 +/- 0.01 (short), 0.86 +/- 0.01 (medium) and 0.87 +/- 0.01 (long), p = 0.003) and augmented thermogenesis (7.6 +/- 1.5 (control) vs 10.5 +/- 2.9 (short), 13.0 +/- 1.9 (medium) and 13.2 +/- 2.8% (long), p = 0.02). Total integrated insulin area above baseline was significantly greater in the long study (short 121, medium 111 vs long 179% of control, p = 0.02). Thus the greatest glycaemic benefit in relation to insulinaemia was obtained with the two shorter insulin infusions (short and medium). In conclusion, this study confirms the role of early prandial insulin secretion (or delivery) in limiting prandial glycaemia in NIDDM and increasing thermogenesis and highlights the pivotal role of the timing of elevation of insulin levels in modulating hyperglycaemia and hyperinsulinaemia.

Aged↗
PubMed1995

Relationships between muscle membrane lipids, fiber type, and enzyme activities in sedentary and exercised rats.

Insulin resistance in skeletal muscle is associated with 1) relative increases in the proportion of glycolytic and fast-twitch muscle fibers and decreases in the proportion of more oxidative fibers and 2) a higher proportion of the saturated fatty acids in membrane structural lipids. Exercise is known to improve insulin action. The aims of the current studies were 1) to investigate the relationship between muscle fiber type and membrane fatty acid composition and 2) to determine how voluntary exercise might influence both variables. In sedentary Wistar rats in experiment 1, increased amounts of unsaturated fatty acids were found in the more oxidative insulin-sensitive red quadriceps and soleus muscles, whereas reduced levels of polyunsaturated fatty acids were found in primarily glycolytic white quadriceps muscles. In experiment 2, voluntary running-wheel exercise by adult female rats over 45 days resulted in reduced proportions of type IIb fibers (P = 0.01) and increased proportions of type IIa/IIx fibers (P = 0.03) in extensor digitorum longus muscle. The magnitude of these changes was related to the distance run (r = -0.73, P = 0.04; r = 0.79, P = 0.02, respectively). Exercise significantly increased oxidative capacity, as assessed by the proportion of intensely NADH-stained fibers (P = 0.0004) and citrate synthase (P = 0.003) and hexokinase (P = 0.04) activities. Citrate synthase activity was also increased by exercise in soleus muscle, where, as expected, no fiber type changes were detected. No significant differences in the fatty acid profile of soleus and extensor digitorum longus were found between groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

A new antidiabetic agent, BRL 49653, reduces lipid availability and improves insulin action and glucoregulation in the rat.

Thiazolidinediones offer promise as oral insulin-sensitizing agents. The effects of a new, high-potency compound (BRL 49653, SmithKline Beecham, Epsom, U.K.) were examined in insulin-resistant (high-fat-fed, HF) and control (high-starch-fed, HS) rats. The diet period was 3 weeks, with a BRL 49653 (10 mumol.kg-1.day-1) or vehicle gavage on the last 4 days. Then basal or euglycemic clamp studies were performed on animals in the conscious fasted state. In the basal state, BRL 49653 produced many similar metabolic responses in HF and HS rats (reduced insulin, glycerol, ketone body, and nonesterified fatty acid levels, reduced whole body glucose turnover, reduced brown adipose tissue glucose metabolism, and increased cardiac glucose metabolism and GLUT4 levels). In contrast, under euglycemic clamp conditions (500 pmol/l insulin), BRL 49653 only induced changes in the HF group (increased glucose infusion rate from 12.2 +/- 0.9 to 21.6 +/- 1.1 mg.kg-1.min-1 [P < 0.001], increased insulin suppressibility of hepatic glucose production [P < 0.01], and increased glucose uptake in muscle [P < 0.01]). BRL 49653 significantly reduced liver but not muscle triglyceride content in HF rats. We conclude that the agent has a general effect on lowering circulating lipid and insulin levels, manifested similarly in normal and insulin-resistant rats, but that enhancement of peripheral insulin action is confined to insulin-resistant rats. Therefore, the hypoinsulinemic action of the thiazolidinediones is probably not related simply to improved peripheral insulin sensitivity. The pattern of individual tissue response to BRL 49653 suggests that altered lipid availability is an important mediator of its effects on glucose metabolism.

3-Hydroxybutyric Acid↗
PubMed1993

The relation between insulin sensitivity and the fatty-acid composition of skeletal-muscle phospholipids.

BACKGROUND: Insulin resistance and hyperinsulinemia are features of obesity, non-insulin-dependent diabetes mellitus, and other disorders. Skeletal muscle is a major site of insulin action, and insulin sensitivity may be related to the fatty-acid composition of the phospholipids within the muscle membranes involved in the action of insulin. METHODS: We determined the relation between the fatty-acid composition of skeletal-muscle phospholipids and insulin sensitivity in two groups of subjects. In one study, we obtained samples of the rectus abdominis muscle from 27 patients undergoing coronary artery surgery; fasting serum insulin levels provided an index of insulin sensitivity. In the second study, a biopsy of the vastus lateralis muscle was performed in 13 normal men, and insulin sensitivity was assessed by euglycemic-clamp studies. RESULTS: In the patients undergoing surgery, the fasting serum insulin concentration (a measure of insulin resistance) was negatively correlated with the percentage of individual long-chain polyunsaturated fatty acids in the phospholipid fraction of muscle, particularly arachidonic acid (r = -0.63, P < 0.001); the total percentage of C20-22 polyunsaturated fatty acids (r = -0.68, P < 0.001); the average degree of fatty-acid unsaturation (r = -0.61, P < 0.001); and the ratio of the percentage of C20:4 n-6 fatty acids to the percentage of C20:3 n-6 fatty acids (r = -0.55, P < 0.01), an index of fatty-acid desaturase activity. In the normal men, insulin sensitivity was positively correlated with the percentage of arachidonic acid in muscle (r = 0.76, P < 0.01), the total percentage of C20-22 polyunsaturated fatty acids (r = 0.76, P < 0.01), the average degree of fatty-acid unsaturation (r = 0.62, P < 0.05), and the ratio of C20:4 n-6 to C20:3 n-6 (rho = 0.76, P = 0.007). CONCLUSIONS: Decreased insulin sensitivity is associated with decreased concentrations of polyunsaturated fatty acids in skeletal-muscle phospholipids, raising the possibility that changes in the fatty-acid composition of muscles modulate the action of insulin.

Aged↗
PubMed1993

In vivo insulin sensitivity of the pyruvate dehydrogenase complex in tissues of the rat.

Activity of the insulin-activated pyruvate dehydrogenase complex (PDHC) is necessary for the complete oxidation of glucose to carbon dioxide or the conversion of glucose to fatty acids in lipogenic tissues. To determine the in vivo insulin sensitivity of PDHC activity in rat tissues, we measured the amount of PDHC in the active form in heart, diaphragm, red quadriceps, white adipose tissue (WAT), and brown adipose tissue (BAT) of rats exposed to five different circulating insulin concentrations under euglycemic clamp conditions. PDHC was measured in mitochondrial extracts of tissues rapidly dissected from rats in the starved state or after euglycemic clamp (4 mM) at insulin infusion rates of 0, 0.125, 0.25, and 2.0 U.kg-1.h-1. Increasing the insulin concentration increased the PDHC activity in all tissues, but the magnitude of this activation was different in different tissues (heart: 3.5-fold; diaphragm: 2.5-fold; red quadriceps: 1.8-fold; WAT: 3.4-fold; and BAT: 10.5-fold). Calculation of the half-maximal effective dose (ED50) for the activation of PDHC produced values that were similar in all tissues (heart: 112 pM; diaphragm: 108 pM; red quadriceps: 146 pM; WAT: 120 pM; and BAT: 118 pM). The insulin sensitivity of PDHC in these tissues correlated particularly well with the ED50 for the insulin effect of decreasing circulating nonesterified fatty acids (NEFA; 122 pM). The differences in the magnitude of the effect of increasing insulin on PDHC activity implies a tissue difference in the requirement for an increased capacity for glucose oxidation after insulin stimulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Adipose Tissue↗
PubMed1993

Effects of blockade of fatty acid oxidation on whole body and tissue-specific glucose metabolism in rats.

We examined the effect of the long-chain fatty acid oxidation blocker methyl palmoxirate (methyl 2-tetradecyloxiranecarboxylate, McN-3716) on glucose metabolism in conscious rats. Fasted animals [5 h with or without hyperinsulinemia (100 mU/l) and 24 h] received methyl palmoxirate (30 or 100 mg/kg body wt po) or vehicle 30 min before a euglycemic glucose clamp. Whole body and tissue-specific glucose metabolism were calculated from 2-deoxy-[3H]-glucose kinetics and accumulation. Oxidative metabolism was assessed by respiratory gas exchange in 24-h fasted animals. Pyruvate dehydrogenase complex activation was determined in selected tissues. Methyl palmoxirate suppressed whole body lipid oxidation by 40-50% in 24-h fasted animals, whereas carbohydrate oxidation was stimulated 8- to 10-fold. Whole body glucose utilization was not significantly affected by methyl palmoxirate under any conditions; hepatic glucose output was suppressed only in the predominantly gluconeogenic 24-h fasted animals. Methyl palmoxirate stimulated glucose uptake in heart in 24-h fasted animals [15 +/- 5 vs. 220 +/- 28 (SE) mumol x 100 g-1 x min-1], with smaller effects in 5-h fasted animals with or without hyperinsulinemia. Methyl palmoxirate induced significant activation of pyruvate dehydrogenase in heart in the basal state, but not during hyperinsulinemia. In skeletal muscles, methyl palmoxirate suppressed glucose utilization in the basal state but had no effect during hyperinsulinemia; pyruvate dehydrogenase activation in skeletal muscle was not affected by methyl palmoxirate under any conditions. The responses in skeletal muscle are consistent with the operation of a mechanism similar to the Pasteur effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Syndromes of insulin resistance in the rat. Inducement by diet and amelioration with benfluorex.

Insulin resistance, mainly in skeletal muscle, is linked to a cluster of prevalent diseases including NIDDM, dyslipidemias, hypertension, and cardiovascular disease. To determine if an oversupply of lipid is associated with the development of skeletal muscle insulin resistance, we examined the effect of the hypolipidemic agent benfluorex in dietary models of insulin resistance. Adult, male Wistar rats were divided into six groups and maintained for 4 wk on diets high in complex carbohydrate, fructose or fat, with or without 50 mg.kg-1.day-1 of benfluorex, given orally. Insulin action was assessed using a hyperinsulinemic (approximately 100 mU/L) euglycemic clamp, with 2-deoxyglucose tracer for individual tissue evaluation, in chronically cannulated conscious animals. Compared with starch feeding, fructose and fat feeding significantly impaired insulin action at the whole-body level (-46% and -41%, respectively, both P < 0.001), as well as in individual skeletal muscles. Fructose feeding increased circulating TGs (by 80%, P < 0.01) but not skeletal muscle TGs; whereas, fat feeding increased skeletal muscle TGs (by 59%, P < 0.01) but not circulating TGs. With benfluorex, however, diet had no effect on circulating and storage TGs; and development of skeletal muscle insulin resistance in the two diet groups was prevented. Feeding fructose but not fat significantly increased mean arterial BP (by 13%, P < 0.05), an effect prevented by benfluorex. These effects support the hypothesis that the development of muscle insulin resistance in these models is linked to local or systemic oversupply of lipid. These diet models--and the parallel effect of benfluorex on insulin resistance, lipids, and hypertension--may prove useful in the search for the mechanisms that underlie the human disorders associated with insulin resistance.

Analysis of Variance↗
PubMed1992

Insulin action and determinants of glycaemia in a rat model of type 2 (non-insulin-dependent) diabetes mellitus.

We aimed to assess prandial responses, basal glucose turnover and insulin action (euglycaemic clamp) in a very low-dose neonatal streptozotocin model of Type 2 (non-insulin-dependent) diabetes mellitus. Male Wistar rats were injected at 2 days of age with 45 mg/kg streptozotocin or vehicle (control). At 8 weeks, the groups were subdivided and fed either a high-fat or high-starch diet for 3 weeks. Both the fat diet and streptozotocin treatments had independent hyperglycaemic effects (streptozotocin/fat 9.3 +/- 0.3 mmol/l; streptozotocin/starch 7.5 +/- 0.3 mmol/l; control/fat 7.4 +/- 0.1 mmol/l; all p less than 0.01 vs control/starch 6.4 +/- 0.1 mmol/l). The fat diet effect was associated with both a reduction in basal glucose clearance (p less than 0.001) and in basal hepatic glucose output (p less than 0.05). Streptozotocin increased basal hepatic glucose output. Significantly higher prandial glycaemia in the streptozotocin/starch group occurred despite similar insulin levels and appeared to be related to an impaired early insulin response. Whole-body and tissue-specific insulin sensitivity were significantly depressed in fat-fed animals compared to starch-fed animals, however there were no significant effects of streptozotocin treatment. We conclude that fasting hyperglycaemia associated with abnormalities in both glucose production and clearance can exist in the presence of a basal hepatic glucose output which is reduced compared to control animals. Furthermore, dietary-fat-induced insulin resistance is not exacerbated by the relative insulin deficiency and/or mild hyperglycaemia observed when dietary fat and neonatal streptozotocin-treatments are combined.

Adipose Tissue↗