Early administration of the glucose-dependent insulinotropic polypeptide receptor antagonist (Pro3)GIP prevents the development of diabetes and related metabolic abnormalities associated with genetically inherited obesity in ob/ob mice

Aims/hypothesis Ablation of gastric inhibitory polypeptide (GIP) receptor action is reported to protect against obesity and associated metabolic abnormalities. The aim of this study was to use prediabetic ob/ob mice to examine whether 60 days of chemical GIP receptor ablation with (Pro³)GIP is able to counter the development of genetic obesity-related diabetes. Materials and methods Young (5–7 weeks) ob/ob mice received once daily i.p. injections of either saline vehicle or (Pro³)GIP (25 nmol kg⁻¹ day⁻¹) over a 60 day period. Food intake, body weight and circulating glucose and insulin were measured at frequent intervals. At 60 days, glucose tolerance, response to native GIP, postprandial responses, insulin sensitivity, HbA_1c, circulating hormones and plasma lipids were assessed. Results Body weight and food intake in (Pro³)GIP-treated mice did not differ from ob/ob controls. GIP receptor blockade significantly improved non-fasting glucose (p < 0.001), HbA_1c (p < 0.05), glucose tolerance (p < 0.001), meal tolerance (p < 0.001) and insulin sensitivity (p < 0.05). Remarkably, (Pro³)GIP treatment prevented the age-related development of diabetes, as none of these parameters differed significantly between treated ob/ob mice and normal age-matched lean controls. Circulating levels of glucagon, corticosterone, adiponectin and total cholesterol were unchanged by (Pro³)GIP, while levels of triacylglycerol, LDL-cholesterol and resistin were decreased (p < 0.05) compared with those in control ob/ob mice. Plasma and pancreatic insulin concentrations were generally lower after (Pro³)GIP treatment than in control ob/ob mice (p < 0.01), but plasma insulin levels remained substantially raised (p < 0.001) compared with those observed in lean controls. Conclusions/interpretation These data indicate that sustained GIP receptor antagonism provides an effective means of preventing the development of many of the metabolic abnormalities of obesity-driven diabetes.     

Active immunization against (Pro3)GIP improves metabolic status in high‐fat‐fed mice

Aim: Ablation of gastric inhibitory polypeptide (GIP) receptor signalling can prevent many of the metabolic abnormalities associated with dietary‐induced obesity‐diabetes. The present study was designed to assess the ability of active immunization against (Pro³)GIP to counter metabolic dysfunction associated with diet‐induced obesity in high‐fat‐fed mice. Methods: Normal male Swiss NIH mice were injected (s.c.) once every 14 days for 98 days with complexed (Pro³)GIP peptide, with transfer to a high‐fat diet on day 21. Results: Active immunization against (Pro³)GIP resulted in circulating GIP antibody production and significantly (p < 0.05 p < 0.01) reduced circulating blood glucose concentrations compared to high‐fat control mice from day 84 onwards. Glucose levels were not significantly different from lean controls. The glycaemic response to i.p. glucose was correspondingly improved (p < 0.01) in (Pro³)GIP‐immunized mice. Furthermore, circulating and glucose‐stimulated plasma insulin levels were significantly (p < 0.01 to p < 0.001) depressed compared to high‐fat control mice. Liver triglyceride, pancreatic insulin and circulating LDL‐cholesterol levels were also significantly reduced in (Pro³)GIP‐immunized mice. These changes were independent of any effects on food intake or body weight. The glucose‐lowering effect of native GIP was annulled in (Pro³)GIP‐immunized mice consistent with the induction of biologically effective GIP‐specific neutralizing antibodies. Conclusion: These results suggest that immunoneutralization of GIP represents an effective means of countering the disruption of metabolic processes induced by high‐fat feeding.     

Dose-dependent efficacy of the glucose-dependent insulinotropic polypeptide (GIP) receptor antagonist GIP(3-30)NH2 on GIP actions in humans

The glucose-dependent insulinotropic polypeptide (GIP) fragment GIP(3-30)NH₂ is a selective, competitive GIP receptor antagonist, and doses of 800 to 1200 pmol/kg/min inhibit GIP-induced potentiation of glucose-stimulated insulin secretion by >80% in humans. We evaluated the effects of GIP(3-30)NH₂ across a wider dose range in eight healthy men undergoing six separate and randomized 10-mmol/L hyperglycaemic clamps (A–F) with concomitant intravenous infusion of GIP (1.5 pmol/kg/min; A–E) or saline (F). Clamps A to E involved double-blinded, infusions of saline (A) and GIP(3-30)NH₂ at four rates: 2 (B), 20 (C), 200 (D) and 2000 pmol/kg/min (E), respectively. Mean plasma concentrations of glucose (A–F) and GIP (A–E) were similar. GIP-induced potentiation of glucose-stimulated insulin secretion was reduced by 44 ± 10% and 84 ± 10% during clamps D and E, respectively. Correspondingly, the amounts of glucose required to maintain the clamp during D and E were not different from F. GIP-induced suppression of bone resorption and increase in heart rate were lowered by clamps D and E. In conclusion, GIP(3-30)NH₂ provides extensive, dose-dependent inhibition of the GIP receptor in humans, with most pronounced effects of the doses 200 to 2000 pmol/kg/min within the tested range.     

Response of incretins (GIP and GLP-1) to an oral glucose load in female and male subjects with normal glucose tolerance

The aim of this study was to analyze the blood glucose profile and the response of incretins in healthy young subjects by the 75 g oral glucose tolerance test (OGTT). We first reported that plasma glucose and GIP levels were higher in males during the early phase of the OGTT.     

Comparison of the anti-diabetic effects of GIP- and GLP-1-receptor activation in obese diabetic (ob/ob) mice: studies with DPP IV resistant N-AcGIP and exendin(1-39)amide

BACKGROUND: The two major incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are being actively explored as anti-diabetic agents because they lower blood glucose through multiple mechanisms. The rapid inactivation of GIP and GLP-1 by the ubiquitous enzyme, dipeptidyl peptidase IV (DPP IV) makes their biological actions short-lived, but stable agonists such as N-acetylated GIP (N-AcGIP) and exendin(1-39)amide have been advocated as stable and specific GIP and GLP-1 analogues. METHODS: The present study examined the sub-chronic (14 days) anti-diabetic actions of single daily doses of N-AcGIP and exendin(1-39)amide given alone or in combination to obese diabetic (ob/ob) mice over a 14-day period. RESULTS: Initial experiments confirmed the potent anti-hyperglycaemic and insulinotropic properties of N-AcGIP and exendin(1-39)amide. Sub-chronic administration of N-AcGIP alone or in combination with exendin(1-39)amide significantly decreased non-fasting plasma glucose and improved glucose tolerance compared to control ob/ob mice. This was associated with a significant enhancement of the insulin response to glucose and a notable improvement of insulin sensitivity. Combined treatment with N-AcGIP and exendin(1-39)amide also significantly decreased glycated haemoglobin. Exendin(1-39)amide alone had no significant effect on any of the metabolic parameters monitored. In addition, no significant effects were observed on body weight and food intake in any of the treatment groups. CONCLUSIONS: The results illustrate significant anti-diabetic potential of N-AcGIP alone and in combination with exendin(1-39)amide.     

The glucose dependent insulinotropic polypeptide response to oral glucose and mixed meals is increased in patients with Type 2 (non-insulin-dependent) diabetes mellitus

Summary Considerable disagreement exists regarding the levels of immunoreactive glucose dependent insulinotropic polypeptide in patients with Type 2 (non-insulin-dependent) diabetes mellitus. Glucose dependent insulinotropic polypeptide levels were therefore studied during oral glucose and mixed meal tolerance tests in normal subjects (n=31) and newly presenting previously untreated patients with Type 2 diabetes mellitus (n=68). The tests were performed in random order after overnight fasts and blood samples were taken at 30 min intervals for 4 h. During the oral glucose tolerance test plasma glucose dependent insulinotropic polypeptide levels increased in the normal subjects from a fasting value of 20±3 pmol/l to a peak of 68±5 pmol/l at 30 min and in the Type 2 diabetic patients from a similar fasting level of 27±3 pmol/l to a higher peak value of 104±6 pmol/l at 30 min (p<0.001). Glucose dependent insulinotropic polypeptide levels were significantly higher in the diabetic patients compared with the normal subjects from 30–90 min (p<0.01–0.001) following oral glucose. During the meal tolerance test glucose dependent insulinotropic polypeptide levels increased in the normal subjects from a pre-prandial value of 22±4 pmol/l to a peak of 93±6 pmol/l at 90 min and in the Type 2 diabetic patients from a similar basal level of 25±2 pmol/l to a higher peak of 133±7 pmol/l at 60 min. Glucose dependent insulinotropic polypeptide concentrations were significantly higher in Type 2 diabetic patients compared with the normal subjects at 30 min (p<0.001), 60 min (p<0.01) and from 210–240 min (p<0.05) during the meal tolerance test. The groups were subdivided on the basis of degree of obesity and glucose dependent insulinotropic polypeptide concentrations were still higher in the diabetic subgroups compared with the normal subjects matched for weight. Type 2 diabetes mellitus is associated with an exaggerated glucose dependent insulinotropic polypeptide response to oral glucose and mixed meals which is independent of any effect of obesity.     

Metabolic effects of sustained activation of the GLP-1 receptor alone and in combination with background GIP receptor antagonism in high fat–fed mice

Aim: Enzyme‐resistant glucagon‐like peptide‐1 (GLP‐1) receptor agonists and GIP receptor antagonists have been proposed to have therapeutic potential for the treatment of type 2 diabetes. Such benefits are based on actions mediated primarily through stimulation of insulin secretion or alleviation of insulin resistance respectively. This study examined the long‐term actions of the stable GLP‐1 receptor agonist (d ‐Ala⁸)GLP‐1 and the GIP receptor antagonist (Pro³)GIP alone and in combination in high fat–fed mice. Methods: Mice on high‐fat diet for 155 days were injected once daily with (d ‐Ala⁸)GLP‐1 or (Pro³)GIP (25 nmol/kg body weight) for 24 days. In the following 24‐day period, half of the (Pro³)GIP‐treated mice were administered an additional dose of (d ‐Ala⁸)GLP‐1 (25 nmol/kg body weight), while the remaining mice continued their original treatment regimes. Results: Daily intraperitoneal injections of (d ‐Ala⁸)GLP‐1 or (Pro³)GIP restored glycaemic control to normal levels and significantly (p < 0.05) improved glucose tolerance compared with high‐fat controls by day 24. Food intake and body weights were not affected. On day 48, all treatment groups displayed significantly improved glucose tolerance (p < 0.05) and insulin sensitivity (p < 0.001) compared with high‐fat controls on day 48. HDL cholesterol levels were significantly increased in mice treated with (d ‐Ala⁸)GLP‐1 alone (p < 0.05) or in combination with (Pro³)GIP (p < 0.01) compared with normal chow‐fed controls. Conclusions: These results illustrate efficacy of (Pro³)GIP and (d ‐Ala⁸)GLP‐1 for treatment of glucose intolerance and insulin resistance caused by high‐fat feeding. Combination therapy appeared to have little benefit over either treatment alone.     

Protective effect of 3-aminobenzamide,an inhibitor of poly (ADP-ribose) synthetase,against streptozotocin-induced diabetes

Summary The addition of 3-aminobenzamide (a potent inhibitor of poly(ADP-ribose)synthetase) into the incubation medium, prevents streptozotocin-induced inhibition of glucose-stimulated insulin release from isolated islets [control 142±14U·islet^–1·h^–1; streptozotocin (0.5mg/ml) 31±8; 3-aminobenzamide (l.0 mg/ml) 96±11; streptozotocin plus 3-aminobenzamide 122±19]. In vivo, intraperitoneal 3-aminobenzamide 300 mg/kg body weight prevents the appearance of overt diabetes in streptozotocin-treated rats. These protective effects of 3-aminobenzamide are dose-dependent and are similar to those exerted by nicotinamide. Taking into account that poly ADP-ribosylation is involved in the repair of damaged DNA, the protection exerted by 3-aminobenzamide against the diabetogenic effect of streptozotocin strongly supports the view that this acute effect may be a major consequence of the activation of DNA repair mechanisms in islet cells.     

Determination and kinetic analysis of non-insulin mediated glucose uptake in Type 1 (insulin-dependent) diabetes mellitus

Summary In man, total glucose uptake is the sum of insulin mediated glucose uptake and non-insulin mediated glucose uptake. The latter pathway has not been examined in Type 1 (insulin-dependent) diabetes mellitus. In order to assess non-insulin mediated glucose uptake in Type 1 diabetes, we measured steady-state rates of glucose uptake during glucose clamps at 5.27, 9.71 and 12.5 mmol/l using low (0.25 mU· kg^–1·min^–1), intermediate (0.75 mU·kg^–1·min^–1) and high (1.50 mU·kg^–1·min^–1) insulin infusion rates in 10 subjects with Type 1 diabetes. For insulin infusion rates of 0.25, 0.75 and 1.50 mU·kg^–1·min^–1 as plasma glucose rose from 5.27 to 9.71 mmol/l, total glucose uptake increased by 35, 43 and 52 percent respectively (p<0.05 for each insulin infusion rate). For all three insulin infusion rates, there was no significant increase in total glucose uptake as plasma glucose increased from 9.71 to 12.5 mmol/l. At each glycaemic level, glucose uptake correlated significantly with plasma free insulin (r=0.81, p<0.01 at 5.71 mmol/l; r=0.84, p<0.01 at 9.71 mmol/l; r=0.73, p<0.02 at 12.5 mmol/l). Linear regression analysis to a point corresponding to plasma free insulin equalling zero, yielded values for non-insulin mediated glucose uptake (mmol·kg^–1·min^–1) of 0.11,0.14,0.18 at plasma glucose of 5.27, 9.7 and 12.5 mmol/l respectively. Thus, increasing plasma glucose concentrations were associated with increasing rates of non-insulin mediated glucose uptake. For each insulin infusion rate used, the percent of total glucose uptake accounted for by non-insulin mediated glucose uptake remained independent of plasma glucose concentration, but decreased as insulin infusion rate increased. During the insulin infusion at 0.25 mU·kg^–1·min^–1, this percentage ranged from 83.7 to 91.4%. Analysis of glucose uptake data derived for theoretical plasma insulin levels of 0, 40, 80 and 160 U/ml yielded linear Eadie-Hofstee plots (r=– 0.83 to – 0.99), suggesting that insulin increased Vmax but did not alter Km. Hence, in these subjects with Type 1 diabetes, glucose uptake, both insulin mediated and non-insulin mediated can be described by Michaelis-Menten kinetics. Comparison of values obtained for Vmax and Km in the present studies of Type 1 diabetes with those obtained from non-diabetic subjects indicates that non-insulin dependent glucose uptake in Type 1 diabetes is quantitatively similar to that of non-diabetic subjects.     

Autoantibodies to the insulin receptor are infrequent findings in Type 1 (insulin-dependent) diabetes mellitus of recent onset

Summary To determine whether autoantibodies to the insulin receptor may represent markers of Type 1 (insulin-dependent) diabetes, the prevalence of such antibodies was investigated in sera of 60 newly diagnosed untreated Type 1 diabetic patients. A sensitive assay, based on enzyme linked immunosorbent assay has been set up which detects antibodies to the insulin receptor irrespective of their potentially inhibiting effect on insulin binding. Moreover, this method allows easy determination of the immunoglobulin class involved in the anti-receptor activity. Among the 60 sera examined, only one was found to contain anti-insulin receptor autoantibodies (IgG class). In view of our data, we conclude that autoantibodies to the insulin receptor are infrequent findings in Type 1 diabetes of recent onset.     

Altered islet Beta-cell function before the onset of Type 1 (insulin-dependent) diabetes mellitus

Summary To define the glucose to insulin dose-response relationship before the onset of diabetes, we studied 22 nondiabetic co-twins of patients with Type 1 (insulin-dependent) diabetes mellitus and nine control subjects. All had intravenous glucose tests at 0.02, 0.1 and 0.5 g/kg and were followedup prospectively for at least 6 years. Seven twins developed diabetes a mean of 7 months later; the remaining 15 are now unlikely to develop diabetes. The seven pre-diabetic twins had higher fasting insulin levels than control subjects (4.2±2.0 vs 1.8±1.8 nmol/l; p<0.05); but lower glucose clearance (1.0±0.5 vs 1.9±0.7 %/min; p<0.05), first phase insulin response at 0.5 g/kg (21.1±23.2 vs 143±50 nmol/l; p<0.0001), and total insulin responses at 0.1 g/kg (p<0.05) and 0.5 g/kg (p<0.00005). Using a curve-fitting programme, the normal glucose to insulin relationship was lost in prediabetic twins who had lower coefficient of determination (R²) than control subjects (p<0.01). In contrast, 15 low-risk twins and their nine control subjects had similar fasting glucose and insulin levels, glucose clearance, R² and insulin secretory responses to different glucose loads. The positive predictive values of subnormal R² and subnormal first phase insulin response were 67 % and 58 % respectively. These observations demonstrate an altered glucose to insulin dose-response relationship and loss of maximum insulin secretory response to glucose before the onset of Type 1 diabetes.     

Radioimmunoassay of Gastric Inhibitory Polypeptide (GIP) and the Effect of Intraduodenal Acidification on Glucose-Stimulated and Unstimulated GIP Release in Humans

GIP was measured by a radioimmunoassay with an antiserum specific for a site within the sequence GIP 15–43. Plasma was precipitated with acetic acid alcohol, and bound and free antigen were separated with polyethylene glycol. The sensitivity (ID 50) was 9.2 pM, corresponding to 46.0 pM in plasma and expressed as the detection limit 2.26 pM and 11.3 pM, respectively. Dilutions of human plasma extracts were parallel to the standard curve, and 80% of the GIP immunoreactivity eluted corresponding to standard GIP by gel chromatography. The effect of duodenal acidification on the glucose-stimulated GIP and insulin release was investigated in man by intraduodenal infusion of glucose with a pH of 6.5 or 1.5 (no. = 7). The GIP concentration in plasma increased from 36.7 (27.5–62.2) to 134 (78.9–215) pM after infusion of glucose with a pH of 6.5 and from 44.6 (23.4–60.5) to 141 (74.0–246) pM after pH 1.5 glucose. Peak values of insulin were 52 (28–73) and 58 (46–122) mU/1, respectively. Infusion of 50 ml 0.1 M HCl intraduodenally (no. = 6) or aspiration of the gastric secretion (no. = 9) for 150 min did not alter the unstimulated GIP concentration in plasma. It is concluded that an acid environment in the duodenum neither potentiates the glucose-induced GIP and insulin release nor influences the unstimulated GIP concentration.     

Enhanced hepatic insulin sensitivity,but peripheral insulin resistance in patients with Type 1 (insulin-dependent) diabetes

Summary Sensitivity to insulin in vivo was studied in 8 normal weight C-peptide negative Type 1 (insulin-dependent) diabetic patients (age 23±1 years, diabetes duration 6±2 years), and in 8 age, weight and sex matched healthy subjects, using the euglycaemic clamp and 3-³H-glucose tracer technique. Prior to the study diabetic patients were maintained normoglycaemic overnight by a glucose controlled insulin infusion. Sequential infusions of insulin in 3 periods of 2 h resulted in mean steady state insulin levels of 12±2 versus 11±1, 18±2 versus 18±2 and 28±3 versus 24±2 U/ml in diabetic patients and control subjects. Corresponding glucose utilization rates were 2.4±0.2 versus 2.4±0.1, 2.4±0.2 versus 3.0±0.3 and 2.9±0.3 versus 4.6±O.6 mg·kg^–1·min^–1, p<0.02. Portal insulin values in the three periods were calculated to 12±2 versus 25±3, 18±2 versus 32±3 and 28±3 versus 37±3 U/ml in the diabetic patients and control subjects using peripheral insulin and C-peptide concentrations and assuming a portal to peripheral insulin concentration gradient of 1 in diabetic patients and of 2.4 in control subjects. Corresponding glucose production rates were 2.5±0.2 versus 2.4±0.1, 1.6±0.1 versus 0.9±0.2 and 0.7±0.1 versus 0.4±0.2 mg·kg^–1·min^–1. Using this approach the insulin dose-response curve for the peripheral glucose utilization was right-ward shifted, while the dose-response curve for the hepatic glucose production as a function of portal insulin levels was left-ward shifted. We conclude that in vivo insulin action is increased in the liver but decreased in peripheral tissues in insulin treated Type 1 diabetic patients. Presumably these oppositely directed changes in insulin action are acquired defects, secondary to the present mode of peripheral insulin treatment.     

Autoantibodies to nervous tissue structures are associated with autonomic neuropathy in Type 1 (insulin-dependent) diabetes mellitus

Summary There is evidence that the immune system may play a role in the pathogenesis of autonomic neuropathy in Type 1 (insulin-dependent) diabetes mellitus. In the present study, we investigated the presence of autoantibodies to sympathetic and parasympathetic nervous structures and their correlation with other conventional autoantibodies in well-characterised diabetic populations, with or without diabetic neuropathy, and normal subjects. An indirect immunofluorescent complement-fixation technique was used, with monkey adrenal gland, rabbit cervical ganglia and vagus nerve as substrates. Of the patients with symptomatic autonomic neuropathy 33% were positive for at least one autoantibody (20% anti-sympathetic ganglia, 10% anti-vagus nerve and 13% anti-adrenal medulla). The frequency of having one or more antibodies to nervous tissues and the prevalence of anti-cervical ganglia antibodies were significantly higher in the neuropathic patients than in the diabetic control subjects with disease of similar duration and in the normal subjects (p<0.05). Of the patients without complications with diabetes of shorter duration 33% were also positive for at least one autoantibody (13% anti-ganglia, 13% anti-vagus nerve and 13% anti-adrenal medulla). No correlation was found with other tissue autoantibodies, including islet cell antibodies. Our data indicate that nervous tissue autoantibodies are associated with symptomatic autonomic neuropathy. Anti-sympathetic ganglia and anti-vagus nerve antibodies seem to be more disease-specific. Patients with diabetes of shorter duration who were positive for these autoantibodies may represent pre-neuropathic patients.     

Nocturnal spikes of growth hormone secretion cause the dawn phenomenon in Type 1 (insulin-dependent) diabetes mellitus by decreasing hepatic (and extrahepatic) sensitivity to insulin in the absence of insulin waning

Summary The aim of the present studies was to test the hypothesis that the dawn phenomenon in Type 1 (insulin-de-pendent) diabetes mellitus is due to a decrease in insulin sensitivity caused by nocturnal spikes of growth hormone. Twelve subjects with Type 1 diabetes were studied on two different occasions, from 24.00 to 02.00 hours, and from 06.00 to 08.00 hours with the euglycaemic clamp technique at two plasma free insulin levels (25 mU/l,n=7; 80 mU/l,n=5). To eliminate the confounding factor of insulin waning of previous Biostator studies, prior to clamp experiments the diabetic subjects were infused with i.v. insulin by means of a syringe pump according to their minute-to-minute insulin requirements. Insulin sensitivity decreased at dawn as compared to the early night hours (30% increase in the rate of hepatic glucose production, 25% decrease in the rate of peripheral glucose utilisation). Plasma insulin clearance did not change overnight. In seven Type 1 diabetic subjects, suppression of nocturnal spikes of growth hormone secretion by somatostatin during basal glucagon and growth hormone replacement resulted in complete abolition of the increased rate of hepatic glucose production at dawn. Replacement of nocturnal spikes of growth hormone faithfully reproduced the increase in hepatic glucose production at dawn of the control study. It is concluded that the dawn phenomenon in Type 1 diabetes mellitus examined during optimal insulin replacement, first, is due solely to a decrease in insulin sensitivity and not to an increase in insulin clearance; second, that the decrease in insulin sensitivity at dawn takes place both in the liver and peripheral tissues; third, that the decrease in hepatic (and most likely extrahepatic) insulin sensitivity at dawn is caused by nocturnal spikes of growth hormone secretion.     

Prevention or delay of Type 1 (insulin-dependent) diabetes mellitus in children using nicotinamide

Summary A controlled trial of oral nicotinamide to prevent the onset of diabetes mellitus in high risk children was conducted in two centres. The selection criteria were age less than 16 years, islet cell antibody 80 IUs, and first phase insulin release < 5th percentile. All of eight untreated control subjects have developed diabetes, whereas only 1 of 14 treated children has diabetes to date. This data suggests that nicotinamide has an effect in preventing Type 1 (insulin-dependent) diabetes and that randomized controlled studies are now indicated.     

A minor subset of HLA-DR3 haplotypes is preferentially increased in Type 1 (insulin-dependent) diabetes

Summary We have been using human T-lymphocyte clones specifically sensitized to detect leucocyte antigens of Type 1 (insulin-dependent) diabetic patients in the hope of detecting novel HLA antigens associated with Type 1 diabetes. We previously described two such clones which define a new class II HLA antigen, Boston-1 (BO1). BO1 is found mainly on cells of persons with particular HLA-DR antigens and, of potential significance for diabetes, BO1 identifies a distinctive subset of DR3 haplotypes. We report here that BO1⁺ DR3 haplotypes are overrepresented in Type 1 diabetes. That is, significantly more of the DR3-positive subjects are BO1-positive in the patient group (31%) than in the control group (8%), suggesting that a diabetes-susceptibility gene may be more common on the BO1⁺ than on the BO1^– DR3 haplotypes. Alternative interpretations are also discussed.     

Normalization of hepatic glucose regulation despite systemic insulin delivery. Studies in patients with pancreatic transplantation for Type 1 (insulin-dependent) diabetes mellitus

Summary With current surgical techniques for pancreatic transplantation, the graft is anastomosed to the iliac vessels, resulting in delivery of insulin to the systemic circulation rather than to the portal vein as in healthy man. The possible influence of the altered route of insulin delivery on the regulation of splanchnic glucose metabolism was studied in four patients with Type 1 (insulin-dependent) diabetes mellitus at 6–19 months after combined pancreatic and kidney transplantation. Four non-diabetic, age-matched renal transplant recipients and two groups of age-matched healthy subjects served as controls. The studies were carried out in the basal state and during two rates of intravenous glucose infusion (2 and 4 mg · kg^–1 · min–1). Fasting arterial glucose and splanchnic glucose output was similar in all groups. Basal hyperinsulinaemia was present in pancreatic graft recipients compared to healthy subjects. During low rate intravenous glucose infusion splanchnic glucose output decreased to a similar extent in all groups. With the higher glucose infusion rate (4 mg · kg^–1 · min^–1) a net glucose uptake was observed which was similar in all three groups. Peripheral glucose uptake was unchanged at the lower glucose infusion rate but increased by 45–55% at the higher rate. It is concluded that despite systemic insulin delivery from a heterotopic pancreatic graft, hepatic glucose metabolism appears normal both in the post-absorptive state and in response to glucose-stimulated endogenous insulin secretion. Portal insulin delivery is thus not necessary for normal hepatic glucose metabolism in the Type 1 diabetic patient.