Christopher M. Asplin

In vivo inhibition of glucagon secretion by paracrine beta cell activity in man.

The close anatomical relationships betaeen pancreatic alpha and beta cells makes possible their interaction at a local (paracrine) level. To demonstrate this in vivo, we have compared the acute glucagon response to intravenous arginine in the basal state and after beta cell suppression by infusions of insulin. The plasma glucose concentration was maintained by the glucose clamp technique. In six normal weight nondiabetics, infusion of insulin at 0.2 mU/kg per min (rate 1) raised the mean +/- SEM plasma insulin levels from 10 +/- 3 to 32 +/- 4 mU/liter and at 1 mU/kg per min (rate 2) raised plasma insulin to 84 +/- 8 mU/liter. This resulted in beta cell suppression, as shown by a diminution in the acute insulin response (incremental area under the insulin response curve, 0-10 min): basal = 283 +/- 61, 199 +/- 66 (rate 1) and 143 +/- 48 mU/liter per 10 min (rate 2) and a fall in prestimulus C-peptide from 1.05 +/- 0.17 to 0.66 +/- 0.15 and to 0.44 +/- 0.15 mM/liter (all P less than 0.01). This beta cell suppression was associated with increased glucagon responses to arginine: 573 +/- 75 (basal), 829 +/- 114 (rate 1), and 994 +/- 136 ng/liter per 10 min (rate 2) and increased peak glucagon responses 181 +/- 11 (basal), 214 +/- 16 (rate 1), and 259 +/- 29 ng/liter (rate 2) (all P less than 0.01). In all subjects, there was a proportional change between the rise in he acute glucagon response to arginine and the fall in the prearginine C-peptide level. To demonstrate that augmented glucagon response was due to betw cell suppression, and not to the metabolic effect of infused insulin, similar studies were performed in C-peptide-negative-diabetics. Their acute glucagon response to arginine was inhibited by the insulin infusion: 701 +/- 112 (basal), 427 +/- 33 (rate 1), and 293 +/- 67 ng/liter per 10 min (rate 2) as was their peak glucagon response: 268 +/- 69, 170 +/- 36, and 115 +/- 33 ng/liter (all P less than 0.01). Thus, hyperinsulinemia, within the physiological range achieved by insulin infusion, inhibits beta cell secretion which, via a paracrine mechanism, potentiates glucagon secretion.

Reduced coxsackie antibody titres in Type 1 (insulin-dependent) diabetic patients presenting during an outbreak of coxsackie B 3 and B 4 infection

SummaryThe potential role of antecedent viral infection in the pathogenesis of Type 1 (insulin-dependent) diabetes was investigated by measuring antibody titres to several viruses in serum obtained at the time of diagnosis of diabetes. An outbreak of Coxsackie B 4 infection folio wed by a wave of Coxsackie B 3 and B 5 infections occurred in Seattle during the time viral serology was obtained in the diabetic patients. Antibody titres to Cocksackie B 5 and Influenza A and B viruses were comparable in diabetics and matched control subjects, but antibody titres to Cocksackie B 3 and B 4 were lower in the diabetics and a low antibody titre to Coxsackie B 3/B 4 was associated with a significantly increased relative risk of diabetes.

Glucose Modulation of Insulin and Glucagon Secretion in Nondiabetic and Diabetic Man

SUMMARY To ascertain whether the ability of glucose to influence the pancreatic islets response to a nonglucose stimulus is normal in type II diabetics, we have evaluated the modulating effect (Md) of the plasma glucose level (PG) on the acute insulin response (IRI) and glucagon response (IRG) to intravenous arginine in noninsulin-dependent diabetics (NIDDM) and nondiabetics (ND). MdIRI or MdIRG is the change in the hormonal response to arginine resulting from changes in plasma glucose level divided by the change in plasma glucose. Md has been determined over two ranges of PG: between normal fasting PG (level I) and mild hyperglycemia (∼160 mg/dl, level II) and between mild hyperglycemia and marked hyperglycemia (∼350 mg/dl, level III). Increases in PG augmented the IRI response in both groups, but the degree of augmentation was impaired in the NIDOM group. MDIRI, for ND and NIDDM between levels I and II were 20 ± 3 and 1.9 ± 0.6, respectively, and between levels II and III were 23 ± 5 and 2.3 ± 0.5, respectively (P < 0.01). MdIRI correlated with fasting PG in ND and NIDDM. Changes in PG resulted in equivalent changes in the IRG response to arginine in both groups. MdIRG for level I to II was −6.1 ±1.0 and −6.0 ± 1.2, and for level II and III was −0.9 ± 0.4 and −1.2 ± 0.5 in ND and NIDDM, respectively. The impairment of MDIRI and its relationship to fasting PG in NIDDM support the hypothesis that fasting hyperglycemia may be, in part, a compensatory mechanism for maintaining beta-cell response to nonglucose stimuli, thereby maintaining basal insulin levels. MdIRG was normal in NIDDM when evaluated at comparable glucose levels in the ND and NIDDM groups.

Coxsackie B4 infection and islet cell antibodies three years before overt diabetes

mechanisms do not explain our finding of a positive correlation of the absolute granulocyte or band counts with the FTs. These two variables may be independently reflecting the severity of the meningitis. However, it is recognized that stimulated granulocytes in patients with bacterial infections produce free radicals such as sUperoxide.13 These free radicals may damage the red cell and alter its deformability. The correlation of the granulocyte count with the FT may indicate that increased free radical release from larger numbers of granulocytes is resulting in enhanced erythrocyte damage. These data confirm the presence of a hemolytic anemia in patients with HI meningitis and suggest that this is related to diminished red cell deformability. The precise mechanism by which the erythrocyte deformability is altered remains speculative. We gratefully acknowledge the technical and editorial assistance of Harry Williams, Raymond Hadley, and James R. Humbert, M.D. The secretarial assistance of Patricia Parucki is also acknowledged,

Beta-Cell Dysfunction in Nondiabetic HLA Identical Siblings of Insulin-Dependent Diabetics

B-cell function was tested in siblings of insulin-dependent diabetics (IDD). From previous studies, it is now recognized that the risk of developing IDD is highest in those sharing both haplotypes (S2H) and lowest in those sharing neither haplotype (SOH) with the diabetic. Insulin secretion in response to intravenous arginine and glucose was evaluated in S2H, SOH, and matched controls. Intravenous arginine and glucose elicited an exaggerated acute phase of insulin secretion in S2H compared with controls when analyzed as incremental insulin area 0–10′, peak level attained, and mean insulin levels postinjection. Insulin responses to arginine and glucose in SOH and matched controls were identical. We hypothesize that the increased beta-cell activity found in S2H predisposes their beta-cells to damage by environmental factors and may be part of the mechanism conferring the increased risk of IDD in S2H.

Glucose regulation of glucagon secretion independent of B cell activity

To investigate whether glucose has an effect on the pancreatic A cell independent of intraislet or paracrine B cell mediation, we have tested the ability of changes in plasma glucose (PG) level to influence the acute glucagon response (AGR) to 5 g of intravenous arginine in 8 C-peptide negative insulin dependent diabetics (IDD). Insulin was infused (1 mU/kg/min) for a 90 min basal period during which PG levels were maintained constant by the glucose clamp technique. Basal AGR was then determined. In 4 of the diabetics, the PG level was subsequently lowered to a new steady state and, in 2 diabetics, PG level was raised. In 2 additional IDDs, two manipulations in PG level were carried out (PG ranges 51-390 mg/dl). The same insulin infusion was continued throughout. The acute glucagon response to arginine was determined at each PG level. The ability of unit changes in PG to influence (modulate) the AGR (MdIRG) was calculated as the difference in AGRs divided by the PG difference. MdIRG was consistent between diabetics (means +/- SEM = 2.1 +/- 0.2) and was independent of both direction and magnitude of the PG change. Thus, in vivo, in man, glucose has an effect on the pancreatic A cell which is independent of intraislet B cell influences.

Insulin, Pancreatic Polypeptide, and Glucagon Antibodies in Insulin-dependent Diabetes Mellitus

To assess the possible value of the use of high-purity pork insulin (HPPI) in the United States, the serum insulin (I), pancreatic polypeptide (PP), glucagon (G), and somatostatin (SRIF) antibody binding characteristics have been determined in 90 conventional insulin-treated diabetic subjects and related to their degree of metabolic control, as assessed by glycosylated hemoglobin (HbA1) concentration. All diabetic subjects had antibodies to insulin, but there was no relationship between any of the antibody binding characteristics and HbA1 level: 47% possessed PP antibodies; mean ± SEM HbA1 in these patients was 14.5 ± 0.3%, identical to those without PP antibodies (14.5 ± 0.4%); 10% had G binding antibodies with HbA1 levels of 14.6 ± 0.8%, similar to those without G antibodies. No subject possessed SRIF antibodies. This lack of correlation between antibody characteristics and metabolic control makes it unlikely that, in the majority of patients, treatment with a less immunogenic insulin (HPPI) versus conventional insulin will result in improved diabetic control.

The Antibody Response to Insulin Therapy: A Prospective Study in HLA-typed Insulin-dependent Diabetic Subjects

There is heterogeneity within insulin-dependent diabetes meliitus (IDDM), and it has been suggested that the presence of the HLA-DR specificities DR3 and DR4 define two subsets of IDDM with clear differences in their immune response to therapeutic insulin. To test this hypothesis, we have prospectively studied the development of insulin binding antibody (IBA) in 54 subjects with newly diagnosed, classical childhood IDDM, determined seven binding constants of their IBA, and measured the presence or absence of pancreatic polypep-tide-binding antibodies after 1 yr of therapy with insulin. There were no relationships between insulin and pancreatic polypeptide antibodies and the DR3 or DR4 specificities whether these specificities were tested for alone or in combination, comparing the presence and absence of DR3 and DR4 and comparing DR3 with DR4, except that of the 33% of all subjects who developed antibodies binding pancreatic polypeptide by 1 yr, none possessed the DR3 specificity alone (P = 0.018). Thus, the hypothesis that the HLA-DR3 and -DR4 specificities are major determinants of IBA formation and, therefore, define important subsets of childhood IDDM in terms of immune response to therapeutic insulin is not substantiated by this study.

How does glucose regulate the human pancreatic A cell in vivo

SummaryTo investigate the mechanism whereby changes in plasma glucose level alter human pancreatic A-cell activity in vivo, A-cell activity was determined during manipulation of plasma glucose and pancreatic B-cell activity by insulin and glucose infusions. A-cell activity (the acute immunoreactive glucagon response to intravenous arginine, 0–10 min) rose from 482±125 to 968±191 pg · ml-1 · 10 min-1 (mean±SEM) when the plasma C-peptide level (a measure of B-cell activity) was suppressed from 2164±365 to 872±162 pg/ml by an insulin infusion at euglycaemia (employing the glucose clamp technique) in six normal subjects. Raising plasma glucose to 6.7 mmol/l during the same insulin infusion returned mean C-peptide (2688±581 pg/ml) and the acute glucagon response to arginine (447±146 pg · ml-1 · 10 min-1) close to basal levels. Individual changes in the acute glucagon response to arginine followed the C-peptide changes. The mean change in the acute glucagon response to arginine per unit change in plasma glucose (-191±36) was similar to that seen when plasma glucose was raised to twice basal levels in six different subjects without an insulin infusion (-159±45). This suggests that, when plasma glucose is raised to about twice basal level in vivo, the major factor in suppressing A-cell activity is the concurrent change in B-cell activity rather than direct effects of glucose or circulating insulin on the A cell.

Diabetes Mellitus Selected Aspects of Pathophysiology and Clinical Practice

The field of diabetes has become extremely broad and difficult to review at any one time. The authors have, therefore, selected six topics in which new insights important to the etiology, pathogenesis, or treatment of diabetes have become evident in the past 2–3 years. Each area attempts to present a coherent statement of new information, its relationship to earlier data, what the clinical implications may be, and what the future is likely to bring. Topics will be chosen in future years based on a judgment that sufficient new information has accumulated to be organized in such a way. No attempt to completely review the literature has been made, but selected references should make it accessible to the interested reader.