Insulin has functions in the brain and dysregulation of these functions may contribute to the expression of late-life neurodegenerative disease. We provide a brief summary of research on the influence of insulin on normal brain function. We then review evidence that perturbation of this role may contribute to the symptoms and pathogenesis of various neurodegenerative disorders, such as Alzheimer's disease, vascular dementia, Parkinson's disease, and Huntington's disease. We conclude by considering whether insulin dysregulation contributes to neurodegenerative disorders through disease-specific or general mechanisms.

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Insulin and neurodegenerative disease: shared and specific mechanisms

Past research indicates that self-control relies on some sort of limited energy source This review suggests that blood glucose is one important part of the energy source of self-control Acts of self-control deplete relatively large amounts of glucose Self-control failures are more likely when glucose is low or cannot be mobilized effectively to the brain (ie, when insulin is low or insensitive) Restoring glucose to a sufficient level typically improves self-control Numerous self-control behaviors fit this pattern, including controlling attention, regulating emotions, quitting smoking, coping with stress, resisting impulsivity, and refraining from criminal and aggressive behavior Alcohol reduces glucose throughout the brain and body and likewise impairs many forms of self-control Furthermore, self-control failure is most likely during times of the day when glucose is used least effectively Self-control thus appears highly susceptible to glucose Self-control benefits numerous social and interpersonal processes Glucose might therefore be related to a broad range of social behavior

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The Physiology of Willpower: Linking Blood Glucose to Self-Control:

• Considerable evidence suggests that the acute effects of antidepressant treatments on brain norepinephrine (NE) and serotonin (5-HT) systems cannot account fully for their delayed therapeutic action. This review evaluates the effects of long-term antidepressant treatment on biogenic amine metabolism and on various indexes of presynaptic and postsynaptic receptor function. In contrast to variable effects on NE and 5-HT turnover and on presynaptic receptor sensitivity, almost all long-term antidepressant treatments produce consistent alterations in a number of measures of postsynaptic amine receptor sensitivity. Longterm treatment has been found to reduce β-adrenergic sensitivity while enhancing responses to serotonergic and α-adrenergic stimulation, suggesting that modulation of receptor sensitivity may be a mechanism of action common to tricyclic antidepressants, "atypical" antidepressants, monoamine oxidase inhibitors, and electroconvulsive therapy. These findings provide support for hypotheses of amine receptor abnormalities in depression and indicate the need for expanded studies of amine receptor function in patients.

Receptor Sensitivity and the Mechanism of Action of Antidepressant Treatment: Implications for the Etiology and Therapy of Depression

Relationship of depression to diabetes types 1 and 2: Epidemiology, biology, and treatment

Problem Evidence from prospective and cross-sectional studies demonstrates that the presence of diabetes doubles the risk of comorbid depression. This commonly overlooked comorbidity affects more than one quarter of the diabetic population, making its recognition and treatment in diabetic patients clinically relevant. Methods PubMed, PsycINFO, and MEDLINE databases were searched (search words: diabetes, depression, metabolic control, hyperglycemia, hypoglycemia) for articles that evaluated outcomes, relationships, and/or management of comorbid depression and diabetes published between 1980 and 2002. This review represents a synthesis of the findings including treatment recommendations. Results Concurrent depression is associated with a decrease in metabolic control, poor adherence to medication and diet regimens, a reduction in quality of life, and an increase in health care expenditures. In turn, poor metabolic control may exacerbate depression and diminish response to antidepressant regimens. Psychotherapy and pharmacotherapy are effective in the presence of diabetes; both cognitive behavior therapy and selective serotonin reuptake inhibitors are weight neutral and have been associated with glycemic improvement in some studies. Conclusion Depression is common in both type 1 and type 2 diabetes and has significant effects on the course and outcome of this medical illness. Conventional antidepressant management strategies are effective and the regimen should be tailored to the individual patient. Enhanced efforts toward good glycemic control may also contribute to improvements in mood and perceptions of well-being.

Depression in diabetic patients: The relationship between mood and glycemic control

A RECENT investigation from this laboratory 1 demonstrated that psychotic depression is associated with low rates of glucose utilization (k) and high levels of serum insulin following glucose injection. Patients with neurotic depression did not demonstrate these abnormalities. This abnormality, a resistance to endogenous insulin, returned toward normal when the patient improved. These findings, which could not be accounted for by initial levels of serum human growth hormone (HGH), age, or nutritional state, suggested that psychotic depression is associated with a type of endogenous insulin resistance unlike that of any previously described condition. Recent studies by Steiner et al 2 and Shaw and Chance 3 have shown that the routine serum insulin radioimmunoassay measures both insulin and the insulin precursor, proinsulin, but that proinsulin is not biologically active until enzymatically degraded to insulin. It is, therefore, possible that the higher serum

Insulin tolerance test in depression.

REPORTS on glucose utilization in depressive illness, as measured by the intravenous glucose tolerance test (GTT), are in conflict. In 1958 pryce 1,2 reported that depressed patients had lower glucose utilization rates (k) than normal subjects. This lowered k was not related to loss of body weight, and it did not change significantly following successful treatment with electroconvulsive therapy (ECT). Herzberg et al in 1968 3 reported, however, no clear association between depression and lowered oral or intravenous GTT. These authors reported no significant change in glucose utilization rate following recovery whether ECT, tryptophan, or no somatic treatment was employed. They attributed previously reported positive findings of the GTT in depression to either malnutrition or inactivity. Pryce's data were more consistent with the report by Van Praag and Leijnse in 1965 4 6 where decreased glucose utilization, as measured by forearm arteriovenous glucose difference, was associated with depressive illness.

Intravenous Glucose Tolerance Test in Depression

Metabolism of carbohydrate and insulin was evaluated in 24 patients with Parkinson's disease before and during L‐dihydroxyphenylalanine (levodopa) therapy. In the untreated state these patients had low rates of glucose utilization (k) and impaired release of insulin during an intravenous glucose tolerance test (GTT). These abnormalities could not be related to age, diet, or degree of neurological disability. In addition these untreated patients had high fasting serum glucose and free fatty acid (FFA), normal human growth hormone (HGH), and low fasting serum insulin levels. It is proposed that the primary abnormality in carbohydrate‐insulin metabolism observed in these parkinsonian patients is a deficit in pancreatic insulin release. Levodopa treatment did not alter the low k and impaired insulin release. A trend toward more normal fasting serum levels of glucose, insulin, and FFA during levodopa therapy was suggested.

Glucose, insulin, and free fatty acid metabolism in Parkinson's disease treated with levodopa.

PREVIOUS reports from this laboratory1-3have described in patients with severe depression an alteration in glucose metabolism which is characterized by resistance to both endogenous and exogenous insulin. This form of insulin resistance appears unlike that of any previously described medical illness and it disappears when the depression is successfully treated with amitriptyline (Elanil). In the course of these studies it was observed that after successful treatment of depression with amitriptyline, the manic-depressive patients demonstrated prolonged hypoglycemia in response to exogenous insulin. At the time of the test four of these six patients demonstrated manic symptoms. This suggested that, in contrast to the insulin resistance of severe depression, mania may be associated with an increased sensitivity to insulin. To examine the possibility that increased insulin sensitivity and other alterations in glucose metabolism are associated with mania, we administered the standard intravenous glucose tolerance test (GTT) and insulin tolerance test

Carbohydrate Metabolism in Mania: Before and After Lithium Carbonate Treatment

SummaryThe effect of in vivo CPZ administration on the in vitro metabolism of the rat epididymal fat pad has been studied. Animals maintained at 22°C for 48 hours sustain a hypothermia following CPZ and their fat pads show increased weight, increased glucose uptake, and decreased glycerol release. When animals are similarly treated and maintained at 31°C, there is no hypothermia and no difference in fat pad weight or metabolism from those of placebo treated animals maintained at 22°C or 31°C. It is concluded that the metabolic changes observed are a consequence of the hypothermia induced by CPZ administration.

Peter S. Mueller

Papers

Insulin tolerance test in depression.

Intravenous Glucose Tolerance Test in Depression

Glucose, insulin, and free fatty acid metabolism in Parkinson's disease treated with levodopa.

Carbohydrate Metabolism in Mania: Before and After Lithium Carbonate Treatment

Effect of Chlorpromazine on Rat Fat Metabolism