Roger H. Unger

Lipotoxicity in the Pathogenesis of Obesity-Dependent NIDDM: Genetic and Clinical Implications

We review evidence that increased tissue levels of fatty acyl CoA cause the β-cell abnormalities of nondiabetic obesity and ultimately result in obesity-dependent diabetes. Nondiabetic obesity in Zucker rats is characterized by hypersecretion of insulin at normal fasting and subfasting glucose concentrations. This is a result of β-cell hyperplasia and increased low Km glucose usage and oxidation. These abnormalities, the hyperinsulinemia, the hyperplasia of β-cells, i.e., its in vitro equivalent, enhanced bromodeoxyuridine incorporation, and the increased low Km glucose usage can be induced by culturing normal islets with 2 mmol/l free fatty acids (FFAs). Once obese Zucker diabetic fatty rats become diabetic, glucose-stimulated insulin secretion (GSIS) is absent and β-cell GLUT2 reduced. Islet triglyceride (TG) content is increased 10-fold, probably reflecting increased FFA delivery (plasma FFA levels > 1.5 mmol/l) beginning about 2 weeks before the onset of diabetes. These β-cell abnormalities, GSIS loss, GLUT2 loss, and TG accumulation, are prevented by reducing plasma FFAs by caloric restriction and by nicotinamide injection. The loss of GSIS and the accumulation of TGs, but not the GLUT2 loss, can be induced in vitro in normal islets cultured in a 2 mmol/l FFA-containing medium, but prediabetic islets seem far more vulnerable to FFA-induced functional impairment and TG accumulation. It is proposed that in uncomplicated obesity, increased lipid availability (FFA levels <1.5 mmol/1) induces both hyperinsulinemia and insulin resistance in parallel fashion, thereby maintaining normoglycemia. A further increase in substrate overload impairs β-cell compensation for insulin resistance and hyperglycemia appears.

Studies of pancreatic alpha cell function in normal and diabetic subjects

The development of a glucagon radioimmunoassay with a relatively high degree of specificity for pancreatic glucagon made possible studies of alpha cell function in healthy nondiabetic subjects and in patients with diabetes mellitus. In the former group mean fasting plasma glucagon averaged 108 mumug/ml (SEM +/-10). In 12 juvenile-type diabetics fasting glucagon averaged 110 (+/-9) and in 33 adult-type diabetics the average was 114 (+/-8). The diabetic averages did not differ significantly from the nondiabetic subjects; however, when hyperglycemia was induced by glucose infusion in the nondiabetic subjects so as to simulate the fasting hyperglycemia of the diabetics, mean glucagon fell to 57 mumug (+/-8), which was significantly below the diabetic mean. In 28 healthy subjects the infusion of arginine elicited a rise in glucagon of at least 100 mumug/ml with a peak level averaging 331 mumug/ml (+/-22) at 40 min. This response to arginine was diminished but not abolished during hyperglycemia induced by simultaneous glucose infusion. In everyone of 45 diabetic subjects tested the infusion of arginine elicited a rise in glucagon of at least 140 mumug/ml to levels significantly greater than in nondiabetics. The peak glucagon level in juvenile-type diabetics averaged 458 mumug/ml (SEM +/-36) and in adult-type diabetics averaged 452 mumug/ml (SEM +/-38). The glucagon response to arginine was unrelated to duration of diabetes, to body weight, type of diabetic treatment, or to other known factors. Marked hyperresponsiveness of glucagon to arginine infusion was observed in two patients with advanced Kimmelsteil-Wilson disease. Glucagon levels were markedly elevated in certain patients with severe diabetic ketoacidosis before treatment with insulin. The findings suggest that alpha cell function is inappropriately increased in diabetes mellitus and could play a significant role in the diabetic syndrome.

Studies of muscle capillary basement membranes in normal subjects, diabetic, and prediabetic patients

A technique is described for the measurement of muscle capillary basement membranes by electron microscopic examination of needle biopsies of the quadriceps muscle. With this procedure it has been possible to obtain an objective evaluation of the significance of capillary basement membrane hypertrophy in diabetic microangiopathy. The results of such studies of muscle capillary basement membrane thickness in 50 normal, 51 diabetic, and 30 prediabetic patients have demonstrated the following. First, that the average capillary basement membrane width of diabetic patients is over twice that of normal subjects; moreover, such basement membrane thickening is a very constant finding among overtly diabetic patients, in that approximately 98% of individual diabetic subjects demonstrated this lesion. The degree of basement membrane thickening in diabetic patients is, however, unrelated to age, weight, severity, or duration of diabetes. Second, capillary basement membrane hypertrophy has been found in approximately 50% of patients who are genetically prediabetic but who have not yet demonstrated evidence of the manifest carbohydrate disturbances of diabetes mellitus. Third, in contrast to the results obtained in genetically diabetic patients, subjects with severe hyperglycemia due to causes other than genetic diabetes only infrequently show basement membrane hypertrophy. These results indicate that thickening of the muscle capillary basement membranes is a characteristic of genetic diabetes mellitus, and further, that the hyperglycemia of diabetes is probably not the factor responsible for the microangiopathy characteristic of diabetes mellitus. Finally, the discovery of thickened capillary basement membranes in prediabetic patients suggests that basement membrane hypertrophy is a relatively early lesion of the diabetic syndrome and provides further support for the conclusion that this vascular defect is independent of carbohydrate derangements of diabetes mellitus.

Abnormal alpha-cell function in diabetes. Response to carbohydrate and protein ingestion.

Abstract The effect of large carbohydrate or protein meals upon plasma glucagon was compared in 14 nondiabetic and 24 diabetic patients. In nondiabetic subjects carbohydrate suppressed mean glucago...

Hyperglycaemia as an inducer as well as a consequence of impaired islet cell function and insulin resistance: implications for the management of diabetes

SummaryIt is postulated that hyperglycaemia influences the natural history of Type 1 (insulin-dependent) and Type 2 (non-insulin-dependent) diabetes mellitus. Hyperglycaemia, even when mild, can attenuate the secretory response of pancreatic β and α cells to increments in glucose and can impair insulin-mediated glucose transport, thus impeding its own correction and initiating a cycle of progressive self-exacerbation and metabolic deterioration. Both reduced islet function and insulin action may be the consequence of a generalized down-regulation and/or occupation of glucose transporters by hyperglycaemia so that the islets respond less to further increments in glycaemia. The postulated hyperglycaemic cycle can be initiated by any environmental perturbation that increases insulin demand in previously normoglycaemic patients in whom insulin secretion has already reached a maximum level of compensation for peripheral insulin resistance (as in obese pre-Type 2 diabetes) or for a reduced β-cell mass (as in pre-Type 1 diabetes). Elimination of hyperglycaemia by any means can halt this cycle of progressive metabolic deterioration and may restore transiently metabolic recompensation both in Type 1 and Type 2 diabetes. There is experimental evidence that long-standing severe hyperglycaemia may irreversibly damage β cells.

Cardiac Steatosis in Diabetes Mellitus A 1H-Magnetic Resonance Spectroscopy Study

Background— The risk of heart failure in type 2 diabetes mellitus is greater than can be accounted for by hypertension and coronary artery disease. Rodent studies indicate that in obesity and type 2 diabetes mellitus, lipid overstorage in cardiac myocytes produces lipotoxic intermediates that cause apoptosis, which leads to heart failure. In humans with diabetes mellitus, cardiac steatosis previously has been demonstrated in explanted hearts of patients with end-stage nonischemic cardiomyopathy. Whether cardiac steatosis precedes the onset of cardiomyopathy in individuals with impaired glucose tolerance or in patients with type 2 diabetes mellitus is unknown. Methods and Results— To represent the progressive stages in the natural history of type 2 diabetes mellitus, we stratified 134 individuals (age 45±12 years) into 1 of 4 groups: (1) lean normoglycemic (lean), (2) overweight and obese normoglycemic (obese), (3) impaired glucose tolerance, and (4) type 2 diabetes mellitus. Localized 1H magnetic resonance spectroscopy and cardiac magnetic resonance imaging were used to quantify myocardial triglyceride content and left ventricular function, respectively. Compared with lean subjects, myocardial triglyceride content was 2.3-fold higher in those with impaired glucose tolerance and 2.1-fold higher in those with type 2 diabetes mellitus (P<0.05). Left ventricular ejection fraction was normal and comparable across all groups. Conclusions— In humans, impaired glucose tolerance is accompanied by cardiac steatosis, which precedes the onset of type 2 diabetes mellitus and left ventricular systolic dysfunction. Thus, lipid overstorage in human cardiac myocytes is an early manifestation in the pathogenesis of type 2 diabetes mellitus and is evident in the absence of heart failure.

Echocardiographic Destruction of Albumin Microbubbles Directs Gene Delivery to the Myocardium

BACKGROUND The noninvasive, tissue-specific delivery of therapeutic agents to the heart would be a valuable clinical tool. This study addressed the hypothesis that albumin-coated microbubbles could be used to effectively deliver an adenoviral transgene to rat myocardium by ultrasound-mediated microbubble destruction. METHODS AND RESULTS Recombinant adenovirus containing beta-galactosidase and driven by a constitutive promoter was attached to the surface of albumin-coated, perfluoropropane-filled microbubbles. These bubbles were infused into the jugular vein of rats with or without simultaneous echocardiography. Additional controls included ultrasound of microbubbles that did not contain virus, virus alone, and virus plus ultrasound. One group underwent ultrasound-mediated destruction of microbubbles followed by adenovirus infusion. Rats were killed after 4 days and examined for beta-galactosidase expression. The hearts of all rats that underwent ultrasound-mediated destruction of microbubbles containing virus showed nuclear staining with 5-bromo-4-chloro-3-indolyl-beta-D-galactopyranoside substrate, indicating expression of the transgene. None of the control animals showed myocardial expression of the beta-galactosidase transgene. By quantitative analysis, beta-galactosidase activity was 10-fold higher in the treated group than in controls (P<0.0001). CONCLUSIONS Ultrasound-mediated destruction of albumin-coated microbubbles is a promising method for the delivery of bioactive agents to the heart.

Diseases of liporegulation: new perspective on obesity and related disorders

Obesity‐related diseases now threaten to reach epidemic proportions in the United States. Here we review in a rodent model of genetic obesity, the fa/fa Zucker diabetic fatty (ZDF) rat, the mechanisms involved in the most common complications of diet‐induced human obesity, i.e., noninsulin‐dependent diabetes mellitus, and myocardial dysfunction. In ZDF rats, hyperphagia leads to hyperinsulinemia, which up‐regulates transcription factors that stimulate lipogene‐sis. This causes ectopic deposition of triacylglycerol in nonadipocytes, providing fatty acid (FA) substrate for damaging pathways of nonoxidative metabolism, such as ceramide synthesis. In β cells and myocardium, the resulting functional impairment and apoptosis cause diabetes and cardiomyopathy. Interventions that lower ectopic lipid accumulation or block nonoxidative metabolism of FA and ceramide formation completely prevent these complications. Given the evidence for a similar etiology for the complications of human obesity, it would be appropriate to develop strategies to avert the predicted epidemic of lipotoxic disorders.—Unger, R. H., Orci, L. Diseases of lipid overflow: new perspective on obesity and related disorders. FASEB J. 15, 312‐321 (2001)

THE ESSENTIAL ROLE OF GLUCAGON IN THE PATHOGENESIS OF DIABETES MELLITUS

The following evidence suggests that diabetes mellitus may not be the simple consequence of relative or absolute insulin deficiency by itself, but may require the presence of glucagon: (1) relative or absolute hyperglucogonaemia has been identified in every form of endogenous hyperglycaemia, including total pancreatectomy in dogs; (2) insulin lack in the absence of glucagon does not cause endogenous hyperglycaemia, but when endogenous or exogenous glucagon is present, it quickly appears, irrespective of insulin levels at the time. These facts are compatible with a bihormonal-abnormality hypothesis, which holds that the major consequence of absolute or relative insulin lack is glucose underutilisation and that absolute or relative glucagon excess is the principal factor in the over-production of glucose in diabetes.

Glucagonocentric restructuring of diabetes: A pathophysiologic and therapeutic makeover

The hormone glucagon has long been dismissed as a minor contributor to metabolic disease. Here we propose that glucagon excess, rather than insulin deficiency, is the sine qua non of diabetes. We base this on the following evidence: (a) glucagon increases hepatic glucose and ketone production, catabolic features present in insulin deficiency; (b) hyperglucagonemia is present in every form of poorly controlled diabetes; (c) the glucagon suppressors leptin and somatostatin suppress all catabolic manifestations of diabetes during total insulin deficiency; (d) total β cell destruction in glucagon receptor-null mice does not cause diabetes; and (e) perfusion of normal pancreas with anti-insulin serum causes marked hyperglucagonemia. From this and other evidence, we conclude that glucose-responsive β cells normally regulate juxtaposed α cells and that without intraislet insulin, unregulated α cells hypersecrete glucagon, which directly causes the symptoms of diabetes. This indicates that glucagon suppression or inactivation may provide therapeutic advantages over insulin monotherapy.