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B C Hansen

Publications and source records attributed to B C Hansen.

At least 55 records · Page 3Linked to original sources
PubMed1995

Pancreatic pathology in non-insulin dependent diabetes (NIDDM).

NIDDM is a heterogeneous disease and subgroups of NIDDM include MODY (Maturity Onset Diabetes of the Young), Malnutrition-related diabetes (MRDM) and Fibrocalculus pancreatic diabetes (FCPD). Endocrine cell population is relatively unchanged in NIDDM: B-cells are reduced by up to 30% and A-cells increased by 10%. Islet amyloid is found in 96% of subjects occupying up to 80% of the islet associated with a reduction in B-cells. Amyloid formation is unlikely to cause diabetes but progressive accumulation increases the severity of the disease. Islet amyloid is formed from the islet amyloid polypeptide (IAPP), a normal constituent of B-cells, co-secreted with insulin. The causal factors for IAPP fibrillogenesis are unknown but abnormal synthesis or overproduction could be involved: stimulation of B-cell secretion in NIDDM by obesity, hyperglycaemia or suphonylurea therapy may promote amyloidosis and further aggravate islet pathology. A mutation of the glucokinase gene in MODY leads to diminished B-cell secretion but not amyloid formation. Diabetes and mutations of mitochondrial DNA is associated with poorly developed islet structure. Exocrine pancreatic size is reduced and there is evidence of sub-clinical chronic pancreatitis in NIDDM. In MRDM and FCPD, chronic pancreatitis and exocrine necrosis is associated with reduced insulin secretion. Unlike cystic fibrosis where islet amyloid is present in diabetic individuals, amyloid is absent from subjects with FCPD. Pathological changes in the exocrine and endocrine pancreas in NIDDM results from and contributes to the pathophysiology of insulin secretion in NIDDM.

Amyloid↗
PubMed1995

Long-term dietary restriction in older-aged rhesus monkeys: effects on insulin resistance.

Long-term dietary restriction to maintain constant body weight in adult rhesus monkeys prevents the development of impaired glucose tolerance, hyperglycemia, and noninsulin-dependent diabetes mellitus. We sought to determine whether these positive antidiabetogenic effects of reduced calorie intake with maintenance of normal lean body weight might be mediated through prevention of the development of insulin resistance. Insulin-stimulated glucose uptake was assessed by the euglycemic hyperinsulinemic clamp technique in seven older-aged rhesus monkeys (20.7 +/- 0.6 years) who had been dietary restricted for 9 +/- 2 years. Results were compared to seven ad libitum-fed nondiabetic monkeys of similar age (21.0 +/- 1.3 years). Results showed that the dietary restricted monkeys had significantly higher in vivo insulin action compared to the ad libitum-fed group (14.06 +/- 2.4 vs 7.75 +/- 0.9 mg/kg FFM/min, respectively; p < .03). We conclude that long-term dietary restriction is an effective means of mitigating the development of significant insulin resistance in older-aged rhesus monkeys, and may be the mechanism underlying the prevention of Type II diabetes in this model.

Aging↗
PubMed1995

Antihypertensive effects of captopril without adverse effects on glucose tolerance in hyperinsulinemic rhesus monkeys.

The rhesus monkey (Macaca mulatta), which has been found to develop spontaneous obesity, non-insulin dependent diabetes mellitus (NIDDM; Type 2), and hypertension, was used to evaluate the potential blood pressure-lowering effects of captopril as well as the specific effects, if any, on the prediabetic state. Intravenous and oral glucose tolerance testing was carried out with oral captopril dosing. Results showed that captopril significantly decreased both systolic and diastolic blood pressure in all monkeys and significantly decreased fasting plasma glucose levels. Based on these preliminary studies in monkeys, we conclude that captopril exerted antihypertensive effects without adverse effects on glucose metabolism.

Animals↗
PubMed1995

Obesity, diabetes, and insulin resistance: implications from molecular biology, epidemiology, and experimental studies in humans and animals. Synopsis of the American Diabetes Association's 29th Research Symposium and Satellite Conference of the 7th International Congress on Obesity, Boston, Massachusetts.

The number of genetic features potentially contributing to the development of obesity and of NIDDM continues to expand, even while evidence from epidemiological studies and prospective longitudinal evaluations of risk factors continue to argue strongly for nongenetic factors in the expression of these disorders. Even as the intensive search goes on for the diabesity gene(s), it is imminently clear that treatment initiatives can and must be oriented to reducing the well-established risk factors, most likely through multiple simultaneous interventions and alterations. Clearly restriction of calories is the most immediately effective of the various tools currently available. The recent results of long-term minimal restriction suggest extraordinary benefits to health can result for those predisposed to the diabesity or insulin resistance syndrome. Changes in diet composition may facilitate maintenance of a lower calorie intake, but in themselves they are not likely to significantly alter the risks of the syndrome, with the exception of lower cholesterol diets for reducing elevated cholesterol levels. Exercise and increased general physical activity must be seen as potentially beneficial; however, because of the magnitude of the physical training activities likely to be effective in lowering insulin resistance on a chronic basis, the expected outcomes from the usual types of relatively limited exercise regimen are less likely to have powerful preventive effects. Nevertheless, the combination of exercise and moderate alterations in caloric intake is likely to have a synergistic beneficial effect. Pharmacological interventions in the insulin resistance syndrome are in their early developmental phases, and we look forward to new developments in this area. Effective anti-obesity agents are greatly needed, and new understanding of the excess risk carried by obesity for many features of the diabesity or insulin resistance syndrome suggest the urgency of greater investment in research toward new modes of therapy. We look forward with great anticipation to the next Obesity, Diabetes, and Insulin Resistance Conference, where new progress in prediction, new understanding of pathogenesis, new genetic markers and modifiers, and new treatment candidates are sure to be forthcoming.

Animals↗
PubMed1994

Chronic calorie restriction alters glycogen metabolism in rhesus monkeys.

Chronic caloric restriction (CR) prevents the development of obesity and maintains health, slows aging processes, and prevents or substantially delays the development of non-insulin-dependent diabetes. Because changes in energy metabolism could be involved in all of these positive effects of CR, we examined glycogen synthase (GS) and glycogen phosphorylase (GP) activities and glucose 6-phosphate (G6P) and glycogen concentrations in skeletal muscle samples before and during a euglycemic hyperinsulinemic clamp in 6 older aged monkeys in which CR had been continued for 10.4 +/- 2.1 years. Basal GS activity (fractional velocity and independent) was significantly higher in the CR monkeys than has been previously shown in normal, hyperinsulinemic and diabetic monkeys. The normal effect of insulin to activate GS was absent in the CR group due to the paradoxical finding in some of these monkeys of a reduction in GS activity by insulin. Insulin also had the unexpected effect of increasing the independent activity of GP above basal activity (p<0.05). There was an inverse relationship between the change (insulin-stimulated minus basal) in GS fractional velocity and GP activity ratio (r=-0.91, p<0.005). The basal independent activities of GS and GP were also inversely correlated (r=-0.79, p<0.05). The insulin-stimulated concentration of G6P tended to be higher than the basal concentration (p<0.06) and was significantly higher than that previously shown in normal monkeys (p<0.05). We suggest that long-term calorie restriction (1) results in alterations in glycogen metabolism that may be important to the anti-diabetogenic and antiaging effects of CR and (2) unmasks early defects which may indicate the likelihood of ultimately developing obesity and diabetes.

Animals↗
PubMed1994

Relationship of skeletal muscle glucose 6-phosphate to glucose disposal rate and glycogen synthase activity in insulin-resistant and non-insulin-dependent diabetic rhesus monkeys.

Reduced insulin action on skeletal muscle glycogen synthase activity and reduced whole-body insulin-mediated glucose disposal rates in insulin-resistant subjects may be associated with an alteration in muscle glucose transport (or phosphorylation) or with a defect distal to glucose 6-phosphate. To examine this issue we determined the glucose 6-phosphate concentration and glycogen synthase activity in muscle samples obtained under basal and euglycaemic hyperinsulinaemic clamp conditions in 27 rhesus monkeys (Macaca mulatta). They ranged from metabolically normal (n = 11) to insulin-resistant (n = 8) to overtly diabetic (non-insulin-dependent) (n = 8). The glucose 6-phosphate measured under insulin-stimulated conditions was inversely correlated to insulin-stimulated glycogen synthase independent activity (r = -0.54, p < 0.005), the change in glycogen synthase independent activity (insulin-stimulated minus basal) (r = -0.58, p < 0.002) and to whole-body insulin-mediated glucose disposal rate (r = -0.60, p < 0.002). The insulin-resistant and diabetic monkeys had significantly higher insulin-stimulated glucose 6-phosphate concentrations (0.57 +/- 0.11 and 0.62 +/- 0.11 nmol/mg dry weight, respectively) compared to the normal monkeys (0.29 +/- 0.05 nmol/mg dry weight) (p's < 0.05). We conclude that under euglycaemic/hyperinsulinaemic conditions, a defect distal to glucose 6-phosphate is a major contributor to reduced whole-body insulin-mediated glucose disposal rates and to reduced insulin action on glycogen synthase in insulin-resistant and diabetic monkeys.

Animals↗
PubMed1994

Hyperinsulinemia is associated with altered insulin receptor mRNA splicing in muscle of the spontaneously obese diabetic rhesus monkey.

The human insulin receptor has two isoforms derived from alternative splicing of exon 11 of the insulin receptor gene. The type B (containing exon 11, or exon 11+) isoform binds insulin with twofold lower affinity than the type A (lacking exon 11, or exon 11-) isoform. In efforts to resolve the controversy over whether altered splicing is involved in the development of insulin resistance and non-insulin-dependent diabetes mellitus (NIDDM), the spontaneously obese diabetic rhesus monkey, a unique model that is extraordinarily similar to human NIDDM, was used. Cross-sectional studies of insulin receptor mRNA splicing variants in vastus lateralis muscle were performed on 19 rhesus monkeys. When monkeys were divided into four groups based upon the known stages of progression to NIDDM: normal (normoglycemic/normoinsulinemic), prediabetic (normoglycemic/hyperinsulinemic), early NIDDM (hyperglycemic/hyperinsulinemic), and late NIDDM (hyperglycemic/hypoinsulinemic), both hyperinsulinemic groups had significantly higher percentages of the exon 11- mRNA splicing variant compared to the normal (74.8 +/- 1.7 vs 59.0 +/- 2.3%; P < 0.005) and late NIDDM groups (74.8 +/- 1.7 vs 64.2 +/- 3.9%; P < 0.05). Our findings provide the first direct evidence linking hyperinsulinemia to alterations in insulin receptor mRNA splicing, and suggest that alterations of insulin receptor mRNA splicing in muscle is an early molecular marker that may play an important role in NIDDM.

Adipose Tissue↗
PubMed1993

Diversity of insulin resistance in monkeys with normal glucose tolerance.

Insulin resistance has been proposed as a critical factor in the development of Type II diabetes, hypertension, dyslipidemia, and coronary artery disease. However, even in normal healthy individuals, a wide range of in vivo insulin action has been found. In the present study we sought to examine this heterogeneity in insulin action in both normal and spontaneously obese nonhuman primates. Maximal insulin responsiveness as measured by a hyperinsulinemic euglycemic clamp, fasting plasma glucose, and insulin levels, beta-cell insulin response to glucose, glucose tolerance, and adiposity were measured in 22 male rhesus monkeys. Results showed that lean animals (body fat < or = 22%) had higher insulin-stimulated glucose uptake (M rate: 14.42+/-1.8 mg/kg FFM/min) compared to obese (8.08+/-0.8). The obese monkeys, with 23-49% body fat, had a wide range of M values (5.32-14.29 mg/kg FFM/min) which showed no relationship to degree of adiposity. In all monkeys, M values had a strong inverse correlation with fasting plasma insulin levels (r=-0.76; p<0.001), but not with fasting glucose or glucose disappearance rate. We conclude that neither degree of obesity above a critical threshold nor range of glucose tolerance is related to insulin resistance; however, in individuals with normal glucose tolerance an early reliable indicator of defective insulin action appears to be fasting insulin concentration. Longitudinal determination of basal insulin levels obtained under standardized conditions so as to minimize extraneous variability is likely to strengthen the ability to predict insulin resistance and possible later development of overt Type II diabetes.

Adipose Tissue↗
PubMed1993

Decreased hepatic insulin extraction precedes overt noninsulin dependent (Type II) diabetes in obese monkeys.

Many obese middle-aged rhesus monkeys (Macaca mulatta) spontaneously develop noninsulin dependent diabetes mellitus (NIDDM). Basal hyperinsulinemia and increased stimulated plasma insulin levels are associated with this obesity and precede the onset of overt diabetes. The present studies sought to determine the relative contributions of enhanced insulin secretion and of reduced insulin clearance to this early obesity-associated hyperinsulinemia. Direct simultaneous measurement of portal and jugular vein insulin levels in two normal monkeys showed a constant rate of hepatic insulin extraction of 56+/-3% over the range of peripheral insulin levels from 351+/-113 to 625+/-118 pmol/L. In 33 additional monkeys ranging from normal to diabetic, basal C-peptide levels were examined as an indicator of beta-cell secretion and the molar ratio of plasma C-peptide to insulin (C/I ratio) under basal steady state conditions calculated as an index of hepatic insulin extraction. Well in advance of overt diabetes, there was a progressive decline of 67% in the apparent hepatic insulin extraction rate in association with increased obesity and plasma insulin levels. Basal insulin levels and hepatic insulin extraction returned toward normal in monkeys with impaired glucose tolerance and in those with overt diabetes. We conclude that reduced insulin disposal, probably due to reduced hepatic extraction of insulin, in addition to increased beta-cell activity, contributes to the development of basal hyperinsulinemia in obese rhesus monkeys progressing toward NIDDM. In addition, in overt diabetes, normal hepatic insulin extraction in the presence of limited beta-cell secretion may exacerbate the hypoinsulinemic state.

Adipose Tissue↗
PubMed1993

Adipose tissue glycogen synthase activation by in vivo insulin in spontaneously insulin-resistant and type 2 (non-insulin-dependent) diabetic rhesus monkeys.

In skeletal muscle, a defect in the covalent activation of glycogen synthase by insulin has been identified in insulin resistance and in Type 2 (non-insulin-dependent) diabetes mellitus, but a similar defect in insulin action at the adipose tissue has not been demonstrated. We sought to determine whether this defect in insulin action in muscle was also present in the same pathway in adipose tissue. We examined the effect of in vivo insulin on adipose tissue glycogen synthase and phosphorylase activity in normal (n = 11), hyperinsulinaemic (n = 8), and impaired glucose tolerant and Type 2 diabetic (n = 8) rhesus monkeys. Adipose tissue samples were obtained before and during a euglycaemic hyperinsulinaemic clamp. Glycogen synthase fractional velocity, independent and total activities were significantly higher in the insulin-stimulated samples compared to the basal samples in the normal group (p < 0.05, respectively). In the hyperinsulinaemic group, however, insulin had no effect on glycogen synthase fractional velocity or independent activity, but did increase the total activity of glycogen synthase and phosphorylase (p < 0.05, respectively). Furthermore, both the basal and the insulin-stimulated total activities of these two enzymes were significantly greater in the hyperinsulinaemic group as compared to both the normal and the diabetic groups (p < 0.05, respectively). In the diabetic group, insulin was without effect on glycogen synthase fractional velocity, independent activity or total activity. We conclude that the covalent activation of adipose tissue glycogen synthase by insulin is absent in both obese hyperinsulinaemic and in spontaneously diabetic monkeys.

Adipose Tissue↗
PubMed1993

Diabetes mellitus in Macaca mulatta monkeys is characterised by islet amyloidosis and reduction in beta-cell population.

Diabetes mellitus in Macaca mulatta rhesus monkeys is preceded by phases of obesity and hyperinsulinaemia and is similar to Type 2 (non-insulin-dependent) diabetes mellitus in man. To relate the progression of the disease to quantitative changes in islet morphology, post-mortem pancreatic tissue from 26 monkeys was examined. Four groups of animals were studied: group I--young, lean and normal (n = 3); group II--older (> 10 years), lean and obese, normoglycaemic (n = 9); group III--normoglycaemic and hyperinsulinaemic (n = 6); group IV--diabetic (n = 8). Areas of islet amyloid, beta cells and islets were measured on stained histological sections. Islet size was larger in animals from groups III (p < 0.01) and IV (p < 0.0001) compared to groups I and II. The mean beta-cell area per islet in micron 2 was increased in group III (p < 0.05) and reduced in group IV (p < 0.001) compared to groups I and II. Mean beta-cell area per islet correlated with fasting plasma insulin (r = 0.76, p < 0.001) suggesting that hyper- and hypoinsulinaemia are related to the beta-cell population. Amyloid was absent in group I but small deposits were present in three of nine (group II) and in four of six (group III) animals, occupying between 0.03-45% of the islet space. Amyloid was present in eight of eight diabetic animals (group IV) occupying between 37-81% of the islet area. Every islet was affected in seven of eight diabetic monkeys. There was no correlation of degree of amyloidosis with age, body weight, body fat proportion or fasting insulin. Islet amyloid appears to precede the development of overt diabetes in Macaca mulatta and is likely to be a factor in the destruction of islet cells and onset of hyperglycaemia.

Aging↗
PubMed1993

Genetics of insulin action.

Insulin action is highly likely to be primarily genetically determined (given a permissive or facilitative environment, for example sufficient calorie availability), as shown by variations in ethnic distribution, evidence for familial transmission and genotypic responses to experimentally induced metabolic stresses. Further, it is likely that the genetic predisposition to insulin resistance is closely linked to (or perhaps synonymous with) the predisposition to develop overt NIDDM. Alternatively, in the development of diabetes, the genetic basis for insulin resistance may be necessary, but not sufficient, requiring a second major gene for beta-cell vulnerability (e.g. exhaustion, deterioration of function, amyloid deposition). The future examination of the genetics of insulin action depends in large measure on the method of assessment of insulin action that is selected and its consistent application to individuals, families and populations. The phenomenological approaches currently being used to describe and define insulin resistance could be identifying many different disorders, all leading to an apparent decrease or impairment of insulin action compared with that in 'normals'. Selection of any method for determining the presence of insulin resistance, together with selection of the threshold for 'present versus absent' is, at best, difficult. It is further complicated by the frequent association of insulin resistance with a wide range of disturbances, including hypertension, dyslipidaemia and glucose intolerance--the insulin resistance 'syndrome'. A number of possible loci and candidate genes controlling insulin action have been studied, and most have been ruled out as the probable underlying cause of the majority of cases of defective insulin action. Among those genes that are unlikely to be determinants of insulin resistance (except in a few rare cases of mutations) are those for insulin, the insulin receptor, glucose transporters and the genes for many specific enzymes. While these are unlikely to be responsible for insulin resistance, such potential genetic defects cannot be fully excluded using present methods. Direct gene sequencing of polymerase-chain-reaction amplified DNA may be the ultimate approach to identifying the critical defects underlying insulin resistance. Other candidate genes regulating insulin action are likely soon to come forth, such as those controlling the generation and function of the intracellular mediators of insulin action.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1993

Insulin-mediated glycogen synthase activity in muscle of spontaneously insulin-resistant and diabetic rhesus monkeys.

Altered insulin action on glycogen synthase activity has been well recognized in non-insulin-dependent diabetes, and some prior evidence has suggested this alteration may be one of the earliest disturbances preceding the development of diabetes. The present study, using the spontaneously insulin-resistant and diabetic rhesus monkey, examined insulin's effect on glycogen synthase at the earliest point of identification of developing diabetes. The normal monkeys (n = 11) had a greater insulin-mediated change in glycogen synthase-independent activity compared with the hyperinsulinemic (n = 8) (P < 0.05) and diabetic (n = 8) (P < 0.01) monkeys. Compared with normal monkeys, the diabetic monkeys had lower basal and insulin-stimulated total glycogen synthase activity (P < 0.05). Monkeys with normal beta-cell responsiveness to intravenous glucose had greater insulin-mediated change in glycogen synthase fractional velocity compared with those with exaggerated (P < 0.01) or absent beta-cell responses to glucose (P < 0.05). We conclude that an alteration in insulin action on glycogen synthase is present as early as beta-cell hyperresponsiveness, one of the earliest detected abnormalities in the progression toward diabetes.

Animals↗
PubMed1993

Chiroinositol deficiency and insulin resistance. I. Urinary excretion rate of chiroinositol is directly associated with insulin resistance in spontaneously diabetic rhesus monkeys.

Previously, we demonstrated that nondiabetic insulin-resistant monkeys had reduced covalent insulin activation of muscle glycogen synthase (GS) compared to normal monkeys and that covalent insulin activation of adipose tissue GS was absent in these monkeys. Covalent insulin activation of muscle and adipose tissue GS in monkeys with impaired glucose tolerance and noninsulin-dependent diabetes (NIDDM) was also absent. As in humans, monkeys with NIDDM have a lower urinary excretion rate of chiroinositol (CI), a component of a putative mediator of insulin action, compared to normal monkeys. To determine whether the urinary excretion rate of CI was related to insulin resistance, which develops naturally in many obese rhesus monkeys, we examined the relationships between 24-h urinary CI excretion rate and 1) whole body insulin-mediated glucose disposal rates (M) and insulin-mediated changes in 2) the skeletal muscle GS activity ratio (sm delta GSAR), 3) the skeletal muscle glycogen phosphorylase activity ratio, and 4) the adipose tissue GS activity ratio (at delta GSAR) in 27 monkeys ranging from normal (n = 12) to insulin resistant (n = 8) to overtly diabetic (n = 7). The urinary CI excretion rate was significantly correlated with M (r = 0.47; P < 0.02), sm delta GSAR (r = 0.38; P < 0.05), skeletal muscle glycogen phosphorylase activity ratio (r = -0.49; P < 0.01), and at delta GSAR (r = 0.46; P < 0.02). The urinary CI excretion rate was also correlated with glucose tolerance (r = 0.39; P < 0.05). There was a wide range of urinary CI excretion rates (0.42-5.17 mumol/day) in monkeys with normal fasting plasma glucose concentrations. However, of the 7 diabetic monkeys, 6 had a urinary CI excretion rate below 2.0 mumol/day, and in the subgroup of 16 monkeys with a urinary CI excretion rate less than 2.0 mumol/day, the associations of urinary CI with M rate (r = 0.65; P < 0.005), glucose tolerance (r = 0.63; P < 0.01), and sm delta GSAR (r = 0.73; P < 0.001) increased in strength and significance. We propose that the urinary CI excretion rate may be 1) a biochemical indicator of both in vivo and in vitro insulin resistance and 2) a noninvasive diagnostic tool with potential for the identification of those individuals at risk for NIDDM and other related diseases with insulin resistance.

Analysis of Variance↗
PubMed1993

Chiroinositol deficiency and insulin resistance. II. Acute effects of D-chiroinositol administration in streptozotocin-diabetic rats, normal rats given a glucose load, and spontaneously insulin-resistant rhesus monkeys.

The acute effects of administration of D-chiroinositol (D-CI), a component of a putative mediator of insulin action, on plasma glucose were examined in low dose streptozotocin-treated rats and normal rats given a glucose load and the effects on plasma glucose and insulin were determined in five obese rhesus monkeys with varying degrees of spontaneous insulin resistance. Single dose intragastric D-CI (10 mg/kg) administered to streptozotocin-treated rats produced a 30-40% decrease in plasma glucose (P < 0.05) at 30-120 min. Single dose intragastric D-CI (2-15 mg/kg) administered to normal rats 2 h before ip glucose produced a 30-50% decrease (P < 0.05) in plasma glucose. D-CI (10 mg/kg) caused a 50% increase (P < 0.05) in glucose disappearance rates in these rats. Myoinositol (10 mg/kg) was without effect. Intravenously administered single dose D-CI (100 mg/kg) increased both the glucose and insulin disappearance rates by 129 +/- 41% (mean +/- SE; P < 0.06) and 89 +/- 39% (P = 0.01), respectively, in all monkeys between 0-30 min compared to control values. D-CI administration, therefore, lowered elevated plasma glucose in streptozotocin-treated hyperglycemic rats, normal rats given a glucose load, and spontaneously insulin-resistant monkeys with or without noninsulin-dependent diabetes mellitus. Intravenous D-CI also lowered plasma insulin in these monkeys.

Animals↗