Ronald A. Arky

Severe hypoglycaemia post-gastric bypass requiring partial pancreatectomy: evidence for inappropriate insulin secretion and pancreatic islet hyperplasia.

Aims/hypothesisPostprandial hypoglycaemia following gastric bypass for obesity is considered a late manifestation of the dumping syndrome and can usually be managed with dietary modification. We investigated three patients with severe postprandial hypoglycaemia and hyperinsulinaemia unresponsive to diet, octreotide and diazoxide with the aim of elucidating the pathological mechanisms involved.MethodsGlucose, insulin, and C-peptide were measured in the fasting and postprandial state, and insulin secretion was assessed following selective intra-arterial calcium injection. Pancreas histopathology was assessed in all three patients.ResultsAll three patients had evidence of severe postprandial hyperinsulinaemia and hypoglycaemia. In one patient, reversal of gastric bypass was ineffective in reversing hypoglycaemia. All three patients ultimately required partial pancreatectomy for control of neuroglycopenia; pancreas pathology of all patients revealed diffuse islet hyperplasia and expansion of beta cell mass.Conclusions/interpretationThese findings suggest that gastric bypass-induced weight loss may unmask an underlying beta cell defect or contribute to pathological islet hyperplasia, perhaps via glucagon-like peptide 1-mediated pathways.

Becoming a Doctor -- Critical-Incident Reports from Third-Year Medical Students

“Critical-incident reports” are short narratives of events judged to be particularly meaningful by participants in the events1–3. Our medical students wrote such reports at the beginning, in the mi...

A Prospective Study of Postmenopausal Estrogen Therapy and Subsequent Incidence of Non-Insulin-Dependent Diabetes Mellitus

The potential influence of postmenopausal estrogen therapy on the subsequent development of non-insulin-dependent diabetes mellitus (NIDDM) is relatively unexplored, despite postulated effects of these hormones on glucose tolerance. We examined the association between postmenopausal hormone use and the subsequent incidence of NIDDM in a prospective cohort of 21,028 postmenopausal US women aged 30 to 55 years and free of diagnosed diabetes, cardiovascular disease, and cancer in 1976. During 12 years of follow-up (422,991 person-years), we confirmed 1249 cases of NIDDM. Current users of postmenopausal hormones had a relative risk of NIDDM of 0.80 (95% confidence interval, 0.67 to 0.96) as compared with never users, after adjustment for age and body mass index (BMI). Past users of these hormones had an age- and BMI-adjusted relative risk of 1.07 (0.93 to 1.23). These results were not materially altered by multivariate adjustment for age, BMI, family history of diabetes, and coronary risk factors. Comparable results were obtained when the analysis was restricted to symptomatic NIDDM as the outcome. We observed no appreciable modification of these associations by family history of diabetes or category of BMI. Duration of current or past use of postmenopausal hormones and dose of conjugated estrogen were not significantly related to incidence of NIDDM. Type of hormone (estrogen alone, progesterone alone, or combination) also did not appear to influence NIDDM risk. These prospective data indicate that postmenopausal hormone therapy is unlikely to be associated with a material increase in the incidence of NIDDM among women.

Parity and incidence of non-insulin-dependent diabetes mellitus

PURPOSE To examine prospectively the association between parity and subsequent incidence of non-insulin-dependent diabetes mellitus (NIDDM). Most previous studies have not controlled for potential confounding by age and obesity. PATIENTS AND METHODS In a prospective cohort study, 113,606 United States registered nurses aged 30 to 55 years and free of diagnosed diabetes, coronary heart disease, stroke, and cancer at baseline were followed for 12 years. Endpoint was incidence of confirmed NIDDM. RESULTS During 1,278,188 person-years of follow-up, we confirmed 2,310 incident cases of NIDDM. An apparent association between parity and diabetes was observed in unadjusted analyses (relative risk = 1.56 [95% confidence interval (CI), 1.27 to 1.91] among women with six or more births compared with that in nulliparous women) (p, trend less than 0.00001). This association was attenuated after adjustment for age (relative risk = 1.19 [CI 0.97 to 1.48], p, trend = 0.06) and was completely abolished after adjustment for both age and body mass index (relative risk = 0.95 [CI 0.75 to 1.19], p, trend = 0.19). Multivariate adjustment for family history of diabetes, age at first birth, hormone use, and other variables did not materially alter these findings. There was no important modifying effect of family history of diabetes on these associations. CONCLUSIONS Despite a temporary diabetogenic effect of pregnancy, parity is not associated with an increased risk of subsequent clinical NIDDM. These data underscore the importance of control for confounding by age and obesity in evaluating these associations.

Alcohol Hypoglycemia: IV: Current Concepts of Its Pathogenesis

Attempts to characterize the hypoglycemia that may follow alcohol ingestion have disclosed the following: The hypoglycemia can be reproduced with pure ethanol and it occurs at blood alcohol levels which do not exceed the range of mild intoxication. It is not attended by plasma changes characteristicof liver damage or peripheral “insulin-like” actions. Circulating immunologically-reactive insulin does not increase and pancreatic responsiveness to islet cell secretogogues such as glucose and tolbutamide is preserved. The hypoglycemia cannot be terminated by glucagon. From infusion experiments, it cannot be ascribed to enhanced peripheral utilization of glucose. In normal humans or dogs, induction of experimental alcohol hypoglycemia with alcohol requires several days of preliminary fasting; in patients with diminished gluconeogenic reserve, regardless of etiology, lesser dietary deprivation is required. Ethanol can also attenuate the prevailing hyperglycemia in fasted “juvenile” diabetics from whom insulin has been withheld to the point of early ketoacidosis. In vitro studies have corroboratedthat at least some of the blood sugar lowering actions of alcohol may be ascribed to a direct impairment in the endogenous formation of glucose from smaller precursors. Oxidative-decarboxylation of added substrates by slices of human, rabbit or rat liver is invariably reduced in the presence of alcohol.Under appropriate conditions, a concomitant inhibition of gluconeogenesis isobserved. It has been proposed that the effects of alcohol upon gluconeogenesis by cellular preparation may be conditioned by the alternative pathways available for reoxidizing the cytoplasmic NADH2 which is generatedduring alcohol oxidation. A pivotal role has been assigned to the prevailing intrahepatic availability and turnover of pyruvate.

Sodium Retention Accompanying Insulin Treatment of Diabetes Mellitus

Urinary sodium excretion before and during insulin therapy was studied in six patients with poorly controlled diabetes. One subject had ketoacidosis; manifestations in the other five ranged from slight ketoacidosis to hyperglycemia alone. All patients retained sodium when diabetes was controlled by insulin, the mean positive sodium balance being 286 mEq. over three days. The diminished urinary sodium excretion did not correlate with the fall in glucosuria or ketonuria; insulin withdrawal studies in two patients indicated that sodium depletion during insulin lack is not a prerequisite for sodium retention during retreatment Im-munoreactive glucagon fell from elevated levels as control of diabetes was established. It is concluded that sodium retention occurs regularly during insulin treatment of poorly controlled diabetes, whether ketoacidosis is present or not. The positive sodium balance should be anticipated when insulin therapy is instituted.

Renin, aldosterone and glucagon in the natriuresis of fasting.

IN view of mans evolutionary origins, it is clear that our ancestors who emerged from the sodium-rich environment of the oceans to dry land had to develop a mechanism to control internal salinity....

Role of Beta-Adrenergic Receptors in Counterregulation to Insulin-induced Hypoglycemia

Since beta-adrenergic blockade dampens the rebound of plasma glucose after insulin-induced hypoglycemia in man but does not affect epinephrine-stimulated hepatic glycogenolysis, studies were undertaken to define further the metabolic role of beta-adrenergic stimulation, particularly its participation in the induction of peripheral insulin resistance by epinephrine. In in vitro studies, propranolol, a specific beta-adrenergic blocker, was shown to prevent both epinephrine and isoproterenol from inducing inhibition of insulin-stimulated glucose uptake by rat hemidiaphragm. Methoxamine, an alpha-adrenergic stimulator, did not alter insulin-stimulated glucose uptake. In man, propranolol blocked the late rise of blood lactate levels which occurs during insulin tolerance tests, indicating that muscle glycogenolysis was prevented and suggesting that propranolol prevents epinephrine from inducing peripheral insulin resistance. This might in part account for the prolonged hypoglycemia observed in propranolol-insulin tolerance tests.

Extreme Hypermagnesemia as a Cause of Refractory Hypotension

A 62-year-old woman with adequate renal function who consumed large quantities of magnesium citrate presented with lethargy and hypotension. The hypotension was refractory to all conventional therapy. Her serum magnesium was 12.5 meq/litre (normal, 1.5 to 2.5). She was found to have a perforated duodenal ulcer; peritoneal aspirate magnesium concentration was 12.2 meq/litre. Hypotension improved with intravenous calcium and peritoneal dialysis. This case shows that hypermagnesemia may be accompanied by severe refractory hypotension, and that intestinal disease may predispose to hypermagnesemia in patients ingesting large quantities of magnesium despite normal renal function. Dialysis removes excess magnesium and reverses its toxic effects.

A New educational approach for supporting the professional development of third-year medical students

This paper describes a new course designed to support the professional development of third-year medical students. The course runs through the clinical clerkships, and has several additional features: it includes a multidisciplinary faculty; it is centrally based in the medical school; it addresses students’ values and attitudes in addition to their knowledge and skills; and it makes use of small-group learning methods, and faculty, student, and group continuity during the year. The curriculum, which addresses ethical, social, and communicative issues in medicine, plus the evaluation of students and of the course, are described.