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D K McCulloch

Publications and source records attributed to D K McCulloch.

At least 37 records · Page 2Linked to original sources
PubMed1991

Non-human pancreas as substrate for cytoplasmic islet cell antibodies.

To investigate qualitative and quantitative differences in islet cell antibody (ICA) detection within and between species we evaluated 8 pancreatic substrates (2 human, 2 baboon, 2 macaque, 1 pig and 1 rat). All substrates were able to detect strongly positive sera (with ICA greater than 160 JDF units). Non-human primate pancreata showed a larger size and greater abundance of islets than human, pig or rat. Significant differences in end point titter were observed both within and between species. In comparing the two best pancreata (1 human and 1 macaque) in masked screening of 50 normal controls and 108 nondiabetic first degree relatives of type 1 diabetics, very similar results were obtained. We concluded that pancreatic substrates from a variety of species may be useful for detection of ICA. This study, however, underscores the need for between and within assay standardization of ICA such as those currently underway in the International Immunology of Diabetes Workshops and Proficiency Tests.

Adult↗
PubMed1991

Effect of nicotinic acid-induced insulin resistance on pancreatic B cell function in normal and streptozocin-treated baboons.

To study the interaction between insulin secretion and insulin action in maintaining glucose homeostasis, we induced experimental insulin resistance in eight normal baboons, in six baboons treated with 40 mg/kg streptozocin (STZ-40), and in six baboons treated with 200 mg/kg streptozocin (STZ-200). Insulin resistance was induced by a 20-d continuous intravenous infusion of nicotinic acid (NA). Normal animals showed compensatory increases in several measures of insulin secretion (fasting insulin [FI], acute insulin response to arginine [AIRarg], acute insulin response to glucose [AIRgluc], and glucose potentiation slope [delta AIRarg/delta G]), with no net change in fasting plasma glucose (FPG) or glycosylated hemoglobin (HbAtc). STZ-40 animals showed compensatory increases in FI, AIRarg, and AIRgluc, but delta AIRarg/delta G failed to compensate. Although FPG remained normal in this group during NA infusion, HbA1c rose significantly. STZ-200 animals failed to show compensatory changes in both AIRgluc and delta AIRarg/delta G, with both HbA1c and FPG rising. These animals showed a paradoxical inhibition of insulin secretion in response to intravenous glucose during NA infusion, at a time when they were hyperglycemic. These data indicate that a significant degree of insulin resistance does not cause hyperglycemia in the presence of normal B cell function but, in animals with reduced B cell mass and superimposed insulin resistance, the degree of hyperglycemia is proportional to the degree of pancreatic B cell dysfunction.

Animals↗
PubMed1991

Correlations of in vivo beta-cell function tests with beta-cell mass and pancreatic insulin content in streptozocin-administered baboons.

In vivo beta-cell function tests are used increasingly in humans during the preclinical phase of insulin-dependent diabetes mellitus (IDDM), but the severity of the beta-cell loss responsible for the abnormalities seen in these tests is unknown. We have measured several physiological beta-cell function tests--fasting plasma glucose, glucose disappearance constant, fasting insulin, acute insulin responses to arginine (AIRarginine) and glucose (AIRglucose), and glucose potentiation of AIRarginine (delta AIRarginine/delta G) and two direct objective measurements (pancreatic insulin content [PIC] and quantitative beta-cell mass)--in adolescent male baboons (Papio anubis/cyanocephalus). We have correlated in vivo measurements obtained within 3 days after the animals were killed with in vitro estimates of PIC and beta-cell mass in 15 animals, (2 nondiabetic requiring insulin treatment and 13 after varying doses of streptozocin to induce degrees of beta-cell damage ranging from normoglycemia to severe hyperglycemia). There was a strong linear correlation between beta-cell mass and PIC (r = 0.79, P less than 0.001). Physiological measures of beta-cell function were significantly correlated with both PIC and beta-cell mass. The correlations between physiological measures and beta-cell mass were linear and intercepted the beta-cell mass axis at 0.15-0.2 g, suggesting that in vivo measures of beta-cell function approach 0 when there is still approximately 40-50% of the beta-cell mass detectable histologically. With PIC, the linear correlations intercepted the axes close to 0. These findings provide considerable validity to the measurements of beta-cell function used in preclinical IDDM in humans.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Prediction and prevention of IDDM--1991.

Although we can now identify some nondiabetic individuals who will subsequently develop clinical insulin-dependent diabetes mellitus (IDDM), our ability to predict subsequent clinical IDDM is far from perfect. In this article, we discuss the status of knowledge regarding the natural history of preclinical IDDM and discuss, especially in relation to predicting IDDM, the genetic, immunologic, and metabolic components of the IDDM disease process.

Biomarkers↗
PubMed1990

Nonprogression of subclinical beta-cell dysfunction among first-degree relatives of IDDM patients. 5-yr follow-up of the Seattle Family Study.

It is unknown among first-degree relatives of individuals with insulin-dependent diabetes mellitus (IDDM) whether the disease process occurs in relatively few but always progresses to clinical IDDM or whether subclinical disease is more common but remains nonprogressive in many cases. Islet cell antibodies (ICAs) were found in 21 of 724 (2.9%) first-degree relatives during screening in the greater Seattle area between 1983 and 1988. Measures of beta-cell function (glucose disappearance rate [Kg], fasting insulin, acute insulin response to intravenous arginine [AIRarg], acute insulin response to intravenous glucose [AIRgluc], slope of glucose potentiation of AIRarg) and insulin sensitivity were obtained. Twenty individuals, 9 ICA+ relatives and 11 ICA- relatives, were evaluated prospectively. When expressed in relation to the expected AIRgluc based on each subject's sensitivity index, AIRgluc in 18 of 20 relatives fell below 100%, indicating inappropriately low insulin secretion (subclinical beta-cell dysfunction). After a median follow-up of 42 mo, 10 of 11 ICA- relatives remained ICA-. None showed deteriorating beta-cell dysfunction, and none developed diabetes. Five ICA+ relatives showed persistent immunologic positivity. beta-Cell function remained remarkably stable in all except 2 relatives. One was a 15-yr-old boy who developed IDDM shortly after screening and before evaluation of beta-cell function could be carried out. The other was an 18-yr-old monozygotic twin who developed IDDM after 27 mo. Both of these individuals had ICAs of 80 Juvenile Diabetes Foundation U and had been discordant for less than 5 yr.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1989

Responses of the pancreatic A cell during hypoglycemia and hyperglycemia are dependent on the B cell.

It is controversial whether stimulation of glucagon secretion by hypoglycemia or suppression by hyperglycemia is a direct effect of glucose on the A cell or whether it is mediated indirectly through the B cell. To determine the role of the B cell in the mediation of glucagon secretion adolescent male baboons were studied before and after successive injections of streptozocin designed to cause B-cell destruction in a series of stages. Following one dose of streptozocin, B-cell function was impaired but fasting blood glucose remained normal. B-cell function declined further with additional doses of streptozocin. As B-cell function declined, there was a corresponding reduction in the glucagon response to hypoglycemia (Ghyp). There were significant correlations between the percentage reduction in Ghyp and the percentage reduction in B-cell function (acute insulin response to arginine, r = .47; acute insulin response to glucose, r = .69; Kg, r = .79). In a second study the ability of hyperglycemia to suppress the acute glucagon response to arginine (AGRarg) was studied. Before streptozocin AGRarg was 128 +/- 26 pg/mL at a glucose level of 80 +/- 4 mg/dL and was suppressed to 74 +/- 20 pg/mL when glucose was raised and clamped at 209 +/- 14 mg/dL. After the initial dose of streptozocin, with mild B cell damage and fasting normoglycemia, AGRarg was not suppressed by hyperglycemia. With severe B cell dysfunction and fasting hyperglycemia, there was paradoxical enhancement of AGRarg by additional hyperglycemia. In conclusion, the ability of the A cell to respond appropriately to hypoglycemia and to arginine during hyperglycemia is dependent on normal B-cell function.

Animals↗
PubMed1989

Decreased insulin- and glucagon-pulse amplitude accompanying beta-cell deficiency induced by streptozocin in baboons.

The effect of beta-cell deficiency on the spontaneous pulsatile secretory pattern of the islets of Langerhans was studied in the baboon. Measures of beta-cell function were correlated with the secretory pattern before and at intervals after streptozocin administration. The degree of insulin deficiency was variable and ranged from mild to moderate. Highly regular pulses were less prevalent in baboons compared with rhesus monkeys and humans, but the mean frequency was similar and was not affected by treatment. The principal effect of beta-cell destruction was to proportionately reduce the pulse amplitude of insulin (-39%, P less than .003) without detectable change in pulse frequency, interhormonal phase relationship, or the regularity of pulses. Glucagon-pulse amplitude also fell (-19%, P less than .09), but not significantly. However, glucagon-pulse amplitude was strongly correlated with insulin-pulse amplitude (r = -.59, P less than .002), whereas mean fasting plasma concentrations of insulin and glucagon were not significantly changed after treatment. Because streptozocin affects only the beta-cell, the data indicate a major influence of the insulin pulse on the alpha-cell secretory pulse. The data do not support the presence of a separate pacemaker for the alpha-cell but do not eliminate this possibility. The strong correlation of reduction in insulin-pulse amplitude with increasing fasting glucose and decreasing glucose disappearance lends support to growing evidence that the pattern of insulin secretion is an important determinant of normal glucose homeostasis.

Animals↗
PubMed1988

Group education for obese patients with type 2 diabetes: greater success at less cost.

It has been suggested that much effort expended in teaching diabetic diets is ineffective and wasteful. We have tested a different system by randomly allocating 75 newly diagnosed obese Type 2 diabetic patients to usual 'unstructured' clinic care or to group education by diabetes specialist nurses and a dietitian. Patients allocated to group education attended five 90-min group sessions during the first 6 months. Six months after diagnosis they had lost more weight (median (95% Cl), 7 (5.5-9) vs 2(1-5)kg, p less than 0.002) and were better controlled (HbA1:7.5 (7.0-8.1) vs 9.5 (8.7-10.4)%, p less than 0.001) than those randomized to the usual clinic system. At 1 year (after no further visits) the difference in weight loss was less (5.5 (4-6.5) vs 3 (2-4) kg, p less than 0.05) and diabetic control was similar (HbA1:9.0(8.2-9.8) vs 9.9(8.9-10.9)%. At 1 year only 14(39%) of the education group and 9(23%) of those attending the clinic had a fasting blood glucose less than 7.0 mmol l-1.

Blood Glucose↗
PubMed1988

Defects in beta-cell function and insulin sensitivity in normoglycemic streptozocin-treated baboons: a model of preclinical insulin-dependent diabetes.

During the preclinical period of human insulin-dependent diabetes, both impaired pancreatic beta-cell function and increased insulin resistance are found, although normoglycemia is preserved. To better understand the changes in beta-cell function and insulin sensitivity that occur in preclinical insulin-dependent diabetes, we performed a panel of in vivo beta-cell function tests and measured insulin sensitivity in adolescent male baboons both in normal health and after a small dose of streptozocin which did not induce hyperglycemia. Nine animals were studied before (stage 1) and 1 week after receiving a low dose of streptozocin (stage 2). There was no change in fasting plasma glucose or insulin. The mean glucose disposal rate (Kg) remained within the normal range, but dropped from 2.0 +/- 0.2% +/- SE) to 1.2 +/- 0.1%/min (P less than 0.01), the acute insulin response to arginine (AIR(arg)) fell from 67.7 +/- 19.4 microU/mL (485.8 +/- 139.2 pmol/L) to 32.8 +/- 7.2 microU/mL (235.3 +/- 51.7 pmol/L; P less than 0.05), and the acute insulin response to glucose (AIR(gluc)) fell from 881 +/- 243 microU/mL.10 min (6321 +/- 1744 pmol/L.10 min) to 334 +/- 82 microU/mL.10 min (2396 +/- 588 pmol/L.10 min; P less than 0.01). The most dramatic change, however, was in the ability of hyperglycemia to potentiate AIR(arg) (expressed as the slope of potentiation). This was reduced by 94% from 1.8 +/- 0.5 to 0.1 +/- 0.1 (P less than 0.01), with almost no overlap in values between stages 1 and 2. Insulin sensitivity was also lower 1 week after streptozocin treatment. When the animals were restudied 8 weeks after streptozocin treatment (stage 3) most measures of beta-cell function were not significantly different from those in stage 1. The fasting plasma glucose level was 85.4 +/- 4.3 mg/dL (4.7 +/- 0.2 mmol/L), Kg was 1.8 +/- 0.3%/min, fasting plasma insulin was 35.9 +/- 8.5 microU/mL (257.6 +/- 61.0 pmol/L), AIR(arg) was 67.0 +/- 15.4 microU/mL (480.7 +/- 110.5 pmol/L), and AIR(gluc) was 615.3 +/- 265.3 microU/mL.10 min (4413 +/- 1901 pmol/L.10 min), and tissue insulin sensitivity was 2.7 +/- 0.4 x 10(4) min/microU.mL. These values show extensive overlap with those of stage 1, from which they are not significantly different. The slope of glucose potentiation, however, remained low in all animals at stage 3.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1987

Beta-cell function and insulin sensitivity in nondiabetic HLA-identical siblings of insulin-dependent diabetics.

Insulin secretion and insulin sensitivity were compared in 12 HLA-identical siblings of insulin-dependent diabetics and nondiabetic controls. Only the maximum acute insulin response to intravenous arginine was lower in the siblings than in the matched controls (P less than .05); other measures of insulin secretion, including the acute insulin response to glucose or arginine, the second-phase insulin response to glucose, and the slope of glucose potentiation, were not significantly different. Insulin sensitivity, derived from an intravenous glucose tolerance test with a minimal-modeling technique, was lower in the siblings (P less than .01). In a large group of nondiabetic controls of various adiposity, insulin secretion and insulin sensitivity were inversely related. In view of the difference in insulin sensitivity between siblings and matched controls, a direct comparison of beta-cell function tests may be inappropriate, and the measures of insulin secretion were compared with those of nondiabetics when adjusted for differences in insulin sensitivity. This analysis revealed that all measures of insulin secretion were significantly lower in the siblings. We conclude that HLA-identical siblings of insulin-dependent diabetics show evidence of both insulin resistance and impaired beta-cell function and that analysis of beta-cell function in relation to insulin sensitivity shows a greater frequency of beta-cell secretory abnormalities than previously appreciated.

Adult↗
PubMed1986

Autoimmunity to insulin, beta cell dysfunction, and development of insulin-dependent diabetes mellitus.

Circulating insulin autoantibodies (INSAAb) were measured in discordant monozygotic twins, first-degree relatives, and other groups at "high risk" for the development of insulin-dependent diabetes mellitus (IDDM), and these results correlated with both islet cell antibody (ICAb) status and beta cell function. INSAAb were positive in 31.6% (12 of 38) ICAb-positive subjects but in only 3.1% (3 of 97) ICAb-negative subjects (X2 = 22.4; P less than 0.001). Elevated levels of INSAAb tended to correlate with younger age and were observed in individuals irrespective of the prevailing degree of their beta cell function. Eight of 15 subjects detected to be INSAAb positive have thus far progressed to clinical IDDM (X2 = 18.3; P less than 0.001). Thus, autoantibodies reactive with the insulin molecule (1) appear to constitute an additional serologic marker of ongoing autoimmunity and development of IDDM, and (2) may reflect heterogeneity in the pathogenesis of IDDM.

Adolescent↗
PubMed1985

A prospective comparison of 'conventional' and high carbohydrate/high fibre/low fat diets in adults with established type 1 (insulin-dependent) diabetes.

Diabetic associations throughout the world are recommending high carbohydrate/high fibre/low fat diets for diabetic patients as a means of improving general health and metabolic control. We have previously shown that the efficacy of a 'conventional' low carbohydrate diet can be greatly increased by improving the method of dietary education. To test whether further improvement in metabolic control could be achieved by changing to a high carbohydrate/high fibre/low fat diet we have followed a group of 40 Type 1 (insulin dependent) diabetic adults for up to 19 months. They had all been prescribed a conventional low carbohydrate diet taught by one of three methods (dietician only, practical lunchtime demonstration or videotape). Those taught by dietician only were left as a control group for follow-up (group A). The others were randomized either to continue on their present diet (group B) or to change to a high carbohydrate/high fibre/low fat diet (group C). At final assessment those in groups B and C were more knowledgeable, compliant and better controlled than group A. Those in group C achieved a change from 38% carbohydrate/43% fat/20 g fibre daily to 45% carbohydrate/34% fat/32 g fibre daily. However, metabolic control in group C deteriorated while taking the high carbohydrate/high fibre/low fat diet (haemoglobin A1 went from 9.4 +/- 0.5% to 11.2 +/- 0.5%, p less than 0.01, over 4 months). None of the patients in group C changed their eating habits or those of their families nearly as much as was recommended.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1985

Assessment of erectile function in diabetic and non-diabetic impotence by simultaneous recording of penile diameter and penile arterial pulse.

Simultaneous monitoring of penile diameter and penile arterial pulse during laboratory-based erotic stimulation with film and fantasy, has been used to compare diabetic and non-diabetic impotent men with non-impotent controls. The degree of erection to erotic film distinguished between organic and psychogenic aetiologies. The diabetic group showed smaller penile pulse amplitude changes than the other two groups. Amongst the diabetics, severe autonomic neuropathy was associated with impaired erectile and penile pulse amplitude responses. Severe retinopathy was associated with smaller baseline penile pulse amplitude as well as smaller amplitude response. Blood pressure response to erotic stimuli did not differ between the three groups. An analysis of the temporal relationship between penile diameter change and pulse amplitude change revealed differences between the groups that may prove to have diagnostic as well as theoretical implications.

Adult↗
PubMed1985

Reduced insulin sensitivity in nondiabetic, HLA-identical siblings of insulin-dependent diabetic subjects.

Nondiabetic, HLA-identical siblings of insulin-dependent diabetic subjects have an increased risk of developing diabetes. Since insulin resistance is present in newly diagnosed diabetic subjects, we studied 12 HLA-identical siblings to determine whether they have impaired insulin sensitivity. Each sibling was carefully matched for age, sex, and body weight to a control from a nondiabetic family. The insulin sensitivity index (SI) was determined after an intravenous glucose tolerance test (IVGTT) using the minimal model of insulin kinetics. The insulin sensitivity index was significantly lower in the HLA-identical siblings compared with their matched controls.

Adolescent↗
PubMed1985

The practice of group psychotherapy with adult insulin-dependent diabetics.

The content and dynamics of two 11-session psychotherapy groups led by physicians for 18 adult patients with insulin-dependent diabetes are described as a guide for others wishing to use this form of treatment. Patients had often found that having diabetes alienated family and friends and many saw their illness as a shameful imperfect state which might at any time be exposed publicly, usually as a result of hypoglycaemia. Our therapy groups, although time consuming for busy physicians, were much shorter than conventional psychotherapy groups but were nevertheless effective in that five patients made good use of the sessions and six moderate use. Powerful feelings were expressed, sad stories told, and self-esteem raised by the acceptance that group members experienced. It is stressed that those wishing to lead psychotherapy groups need both training and supervision.

Adult↗