Insulin secretion and glucose disappearance rate were measured in 66 subjects with a wide range of fasting plasma glucose levels. The acute insulin response was present in subjects with fasting glucose levels below 115 mg/dl but was absent above this level. The glucose disappearance rate related to the relative acute insulin response in subjects with fasting glucose below 115 mg/dl and to total insulin response when fasting glucose levels were above 115 mg/dl. A calculated glucose disappearance rate of 1.06 per cent per minute was found when the acute isulin response was zero. All subjects with fasting glucose levels greater than 115 mg/dl had glucose disappearance rates greater than 1.06. These studies support 1) epidemiological data indicating 115 mg/dl as an upper limit of normal for fasting plasma glucose levels and 1.0 per cent per minute as a lower limit of normal for the glucose disappearance rate, and 2) evidence for an important role for the acute insulin response in the determination of glucose disappearance rates during intravenous glucose tolerance tests.
A B S T R A C T To determine whether endogenous alphaadrenergic activity contributes to abnormal insulin secretion in nonketotic, hyperglycemic, diabetic patients, alpha-adrenergic blockade was produced in normal and diabetic subjects. The diabetics had a significantly (P < 0.01) greater increase in circulating insulin 1 h after an intravenous phentolamine infusion than did the normal subjects. During the phentolamine infusion, there was also a significant augmentation of acute insulin responses to intravenous glucose (20 g) pulses in normal subjects (P < 0.05) and diabetics (P < 0.02); this augmentation was fivefold greater in the diabetics. Simultaneous treatment with the beta-adrenergic blocking agent, propranolol, did not alter these findings. Thus a role for exaggerated endogenous alpha-adrenergic activity in abnormal insulin secretion of the diabetic subjects is suggested. To determine whether this alphaadrenergic activity might be related to elevated circulating catecholamines, total plasma-catecholamine levels were compared in normal and nonketotic diabetic subjects given intravenous glucose pulses. These levels were significantly greater (P < 0.02) in the diabetic compared to the normal group before the glucose pulse, and increased significantly in both groups (P < 0.02 and < 0.001, respectively) after the pulse. These data suggest that excessive catecholamine secretion may lead to an abnormal degree of endogenous alpha-adrenergic activity, which contributes to defective insulin secretion in diabetic subjects.
After successful pancreas transplantation, recipients with type I diabetes mellitus achieve a return to normal fasting plasma glucose levels, normal oral glucose tolerance tests, and normal levels of HbA,C (1-7). However, whether recipients undergo alterations in counterregulatory hormonal responses to glycopenia, or improvement in counterregulation of hypoglycemia, has not been determined. These are important considerations because type I diabetic patients commonly have defective glucagon and epinephrine responses to hypoglycemia and, consequently, deranged counterregulation of hypoglycemia with its attendant risks (8-13). Therefore, presence or absence of improvement in these responses are highly relevant factors in the evaluation of the overall benefits of pancreas transplantation. Moreover, since the transplanted pancreas is denervated and since islet alpha cell and pancreatic polypeptide cell function is neurally modulated, investigation of pancreas recipients offers a unique opportunity to assess regulation ofglucagon and pancreatic polypeptide secretion from the pancreas in humans in the setting of absent central nervous system input into the islet.To evaluate hormonal counterregulation of hypoglycemia in patients with type I diabetes mellitus who have received successful pancreas allografts, we have examined glucose, glucagon, pancreatic polypeptide, and catecholamine responses during insulin-induced hypoglycemia. We have also assessed glucagon and pancreatic polypeptide responsivity to direct stimulators of alpha and pancreatic polypeptide cells (arginine and secretin, respectively) to ascertain whether possible alterations in secretory responses in pancreas recipients are specific for hypoglycemic signaling or more general in nature. In this study, the responses of pancreas recipients were compared with responses of patients with similar durations of type I diabetes mellitus, who had not received pancreas transplantation, and to nondiabetic control subjects. MethodsSubjects. 38 type I diabetic recipients of pancreas allografts with iliac vessel anastomoses and with intact native pancreases who had been transplanted between 3 and 60 mo previously were studied (Table I). All recipients were normoglycemic, had normal hemoglobin A,C levels and mildly elevated serum creatinine levels, and none were receiving exogenous insulin or other medication for diabetes. Immunosuppression was achieved with the triple-drug regimen of azathioprine, cyclosporine, and prednisone (14). 54 patients with type I diabetes and with similar age, sex distribution, body-mass index, serum creatinine levels, and duration ofdiabetes, as well as 26 normal volunteers of similar age, sex distribution, and body-mass index, were studied to obtain control data. All subjects were admitted to the University
These data suggest that in African-American children, family history of type 2 diabetes is a risk factor for insulin resistance. These children manifest important metabolic alterations, including impaired insulin-stimulated total and nonoxidative glucose disposal early in the first decade of life. We propose that this familial tendency, combined with environmental influences, could lead to type 2 diabetes decades later.
Clonidine is an antihypertensive drug that markedly suppresses plasma catecholamine levels. In an attempt to investigate the effects of suppression of endogenous catecholamine secretion on glucose homeostasis and glucoregulatory hormones, we administered oral clonidine to 20 normal male subjects, two patients with transsections of the cervical spinal cord, and one patient with an insulinoma. Unexpectedly, after a single dose of 0.5 ing. given to normal subjects, insulin concentrations fell and plasma glucose rose 12 ± 1 mg./dl. (p < 0.001; n = 6) without an increase in glucagon. After four days of clonidine treatment, plasma glucose again was elevated (Δ = +11 ± 3 mg./dl.; p < 0.01), while basal plasma insulin and glucagon levels remained unchanged. The acute insulin response to an intravenous glucose injection of 5 gm. decreased from 33 ± 7 to 11 ± 2 μU./ml. (n = 8; p < 0.01), and KG declined from 0.80 ± 0.13 to 0.53 ± 0.06 per cent per minute (p < 0.01). Similar responses were seen in the paraplegic patients. In contrast, expected responses to clonidine were not observed in the insulinoma patient preoperatively; these normal responses were restored after resection of the tumor. All metabolic alterations induced by clonidine were reversed by infusion of phentolamine, an alpha-adrenergic blocking agent. We conclude that clonidine causes hyperglycemia and inhibits insulin secretion through an alpha-adrenergic mechanism. Since plasma catecholamine concentrations and vascular tone were markedly reduced by clonidine, this drug appears to selectively stimulate metabolic adrenergic pathways different from those operative in vasomotor regulation.
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