DAYAL NARAYAN, MBBS, Junior Resident; &  SHAHUL AMEEN, M.D., Senior Resident; Central Institute of Psychiatry, Ranchi, India.

INTRODUCTION

A ‘diabetes epidemic’ is underway with a worldwide estimate of people having diabetes mellitus (DM) being 30 million in 1985, 135 million in 1995 and 177 million in 2000 and a predicted figure of 370 million by the year 2030. Much of this increase will occur in developing countries and in people in their most productive years. The corresponding figures for India are 32 million (2000) and 81 million (2030). Deaths attributed to diabetes (4 million per year) account for nine percentage of total deaths worldwide. DM is the sixth leading cause of death above 60 years, and seventh across all age groups in developed countries and is an important risk factor the leading causes of mortality i.e., ischemic heart disease, hypertensive heart disease and cerebrovascular disease (WHO, 2003). Diabetes and its potentially preventable long-term complications result in direct (to the individual and the health care system, for medical care) and indirect (lost productivity) costs that account for a significant portion of health care budgets. Intangible costs (including pain, anxiety, inconvenience and decreased quality of life) are equally significant but difficult to quantify.

Globally, neuropsychiatric conditions account for 19% of disease burden among adults. Unipolar depressive disorder, schizophrenia and bipolar affective disorder come in first, sixth and 10th positions respectively among the 10 leading causes of YLD (years lost in disease) estimate for 2002. Increasing burden of noncommunicable diseases, accounting for more than nearly half of the global burden of disease (all ages) is occurring mostly in the middle-income countries (Mathers et al., 2003). Interrelationships of DM and psychiatric disorders have long been noted by careful observers like Sir Henry Maudsley who commented “Diabetes is a disease which often shows itself in families in which insanity prevails” (The Pathology of the Mind, 1899).

Diabetes mellitus

Diabetes mellitus is a group of metabolic diseases characterized by hyperglycemia due to absolute or relative deficiency of insulin resulting from defects in insulin secretion, insulin action, or both. The chronic hyperglycemia of diabetes is associated with long-term damage, dysfunction, and failure of various organs, especially the eyes, kidneys, nerves, heart, and blood vessels.

Classification of diabetes (American Diabetes Association, 2004)

I. Type 1 diabetes (ß-cell destruction, usually leading to absolute insulin deficiency)

          A. Immune mediated

          B. Idiopathic

II. Type 2 diabetes (may range from predominantly insulin resistance with relative insulin deficiency to a predominantly secretory defect with insulin resistance)

III. Other specific types

          A. Genetic defects of ß-cell function

          B. Genetic defects in insulin action

          C. Diseases of the exocrine pancreas

          D. Endocrinopathies

          E. Drug- or chemical-induced

          F. Infections

          G. Uncommon forms of immune-mediated diabetes

          H. Other genetic syndromes sometimes associated with diabetes

IV. Gestational diabetes mellitus (GDM)

Type 1 diabetes or immune-mediated diabetes accounts for 5–10% of cases of diabetes. Also known by many other names (insulin-dependent diabetes, type I diabetes, or juvenile-onset diabetes) it results from a cellular-mediated autoimmune destruction of the ß-cells of the pancreas. Markers of the immune destruction (islet cell autoantibodies, autoantibodies to insulin, autoantibodies to glutamic acid decarboxylase (GAD65), and autoantibodies to the tyrosine phosphatases IA-2 and IA-2ß) are present in 85–90% of these individuals. It has strong HLA associations, with linkage to the DQA and DQB genes. The rate of ß-cell destruction may be rapid (infants and children) or slow (mainly adults). Ketoacidosis may be the first manifestation of the disease (especially in children and adolescents), while modest fasting hyperglycemia can rapidly change to severe hyperglycemia and/or ketoacidosis in the presence of infection or other stress in others. In the later stage of the disease, there is little or no insulin secretion, as manifested by low or undetectable levels of plasma C-peptide. Immune-mediated diabetes commonly occurs in childhood and adolescence, but it can occur at any age, even in the ninth decade of life. Although patients are rarely obese when they are diagnosed, the presence of obesity is not incompatible with the diagnosis. They are also prone to other autoimmune disorders such as Graves’ disease, Hashimoto’s thyroiditis, Addison’s disease, vitiligo, celiac sprue, autoimmune hepatitis, myasthenia gravis, and pernicious anemia.

Idiopathic type 1 diabetes: This rare group has permanent insulinopenia and are prone to ketoacidosis but without evidence of autoimmunity. Most are of African or Asian origin, suffer from episodic ketoacidosis and exhibit varying degrees of insulin deficiency between episodes. This form of diabetes is strongly inherited, lacks immunological evidence for ß-cell autoimmunity, and is not HLA associated. An absolute requirement for insulin replacement therapy in affected patients may come and go.

Type 2 diabetes (previous terms: non-insulin-dependent diabetes, type II diabetes, or adult-onset diabetes) accounts for 90–95% of those with diabetes. It encompasses individuals who have insulin resistance and usually have relative (rather than absolute) insulin deficiency. At least initially, and often throughout their lifetime, these individuals do not need insulin treatment to survive. Although the specific etiologies are not known, there are probably many. Autoimmune destruction of ß-cells does not occur, and patients do not have any of the other causes of diabetes listed. Most patients are obese, and obesity itself causes some degree of insulin resistance. Patients who are non-obese may have an abdominal pattern of fat distribution. Insulin secretion is defective and insufficient to compensate for insulin resistance. Insulin resistance may improve with weight reduction and/or pharmacological treatment of hyperglycemia but is seldom restored to normal. It is often associated with a strong genetic predisposition, more so than is the autoimmune form of type 1 diabetes. However, the genetics of this form of diabetes is complex and not clearly defined. Ketoacidosis seldom occurs spontaneously, and when seen, it usually arises in association with stress such as infection. Type 2 diabetes frequently goes undiagnosed for many years because the hyperglycemia develops gradually and at earlier stages is often not severe enough to produce any noticeable classic symptoms of diabetes though the increased risk of developing complications still exists. Identified risk factors include age more than 45 years, overweight (BMI > 25 kg/m2), family history of diabetes (i.e., parents or siblings with diabetes), habitual physical inactivity, race/ethnicity, previously identified IFG (impaired fasting glucose) or IGT (impaired glucose tolerance), history of GDM or delivery of a baby weighing >9 lbs, hypertension (>140/90 mmHg in adults), HDL cholesterol <35 mg/dl and/or a triglyceride level >250 mg/dl, polycystic ovary syndrome and history of vascular disease.

Other specific types of diabetes

Genetic defects of the ß-cell. Maturity-onset diabetes of the young (MODY), characterized by impaired insulin secretion (with minimal or no defects in insulin action) is associated with monogenetic defects in ß-cell function and onset of hyperglycemia generally before 25 years. Inheritance is autosomal dominant. The most common genetic abnormalities are mutation on chromosome 12 (hepatocyte nuclear factor (HNF)-1) and chromosome 7p (glucokinase gene). Point mutations in mitochondrial DNA have been found to be associated with diabetes mellitus and deafness. Genetic abnormalities with the inability to convert proinsulin to insulin inherited in an autosomal dominant pattern leads to mild glucose intolerance.

Genetic defects in insulin action: The unusual metabolic abnormalities associated with mutations of the insulin receptor may range from hyperinsulinemia and modest hyperglycemia to severe diabetes. Some may have acanthosis nigricans. Women may be virilized and have enlarged, cystic ovaries.

Diseases of the exocrine pancreas: Acquired processes include pancreatitis, trauma, infection, pancreatectomy, and pancreatic carcinoma. Damage to the pancreas must be extensive for diabetes to occur except in adrenocarcinomas. Extensive cystic fibrosis and hemochromatosis, fibrocalculous pancreatitis are other causes.

Endocrinopathies: Excess of several hormones (e.g., growth hormone, cortisol, glucagon, epinephrine) that antagonize insulin action (e.g., acromegaly, Cushing’s syndrome, glucagonoma, pheochromocytoma, respectively) can cause diabetes. This generally occurs in individuals with preexisting defects in insulin secretion, and hyperglycemia typically resolves when the hormone excess is resolved. Somatostatinoma- and aldosteronoma-induced hypokalemia can cause diabetes, at least in part, by inhibiting insulin secretion. Hyperglycemia generally resolves after successful removal of the tumor.

Drug- or chemical-induced diabetes: Many drugs can precipitate diabetes in individuals with insulin resistance. Intravenous pentamidine can permanently destroy pancreatic ß-cells. Nicotinic acid and glucocorticoids can impair insulin action. Alpha-interferon has been associated with islet cell antibodies and severe insulin deficiency.

Infections: Certain viral infections (congenital rubella, Coxsackie virus B, cytomegalovirus, adenovirus, and mumps) have been associated with ß-cell destruction and diabetes.

Uncommon forms of immune-mediated diabetes: Conditions like the stiff-man syndrome and systemic lupus erythematosus show anti-insulin receptor antibodies.

Other genetic syndromes sometimes associated with diabetes: Genetic syndromes like Down’s syndrome, Klinefelter’s syndrome, and Turner’s syndrome are accompanied by an increased incidence of diabetes mellitus. Wolfram’s syndrome (autosomal recessive disorder with diabetes insipidus, hypogonadism, optic atrophy, and neural deafness) is characterized by insulin-deficient diabetes and the absence of ß-cells at autopsy.

Gestational diabetes mellitus (GDM) is defined as any degree of glucose intolerance with onset or first recognition during pregnancy regardless of whether insulin or only diet modification is used for treatment or whether the condition persists after pregnancy or the possibility that unrecognized glucose intolerance may have antedated or begun concomitantly with the pregnancy. The prevalence may range from 1 to 14% of pregnancies and represents nearly 90% of all pregnancies complicated by diabetes.

Clinical features

Clinical manifestations include the classical triad of polyuria, polydypsia, and polyphagia; weakness and weight loss; and in some patients, features of diabetic ketoacidosis or hyperosmolar nonketotic coma. Some patients may present with the long-term complications such as retinopathy (diminished vision, blindness), nephropathy (and end stage renal disease), or neuropathy (sensory, motor, autonomic).

Diagnosis of diabetes (American Diabetes Association, 2004)

2-h PG = 2-h Postload Glucose; FPG = Fasting Plasma Glucose; IGT = Impaired Glucose Tolerance; IFG = Impaired Fasting Glucose

*FPG is preferred because of ease of administration, convenience, acceptability to patients, and lower cost. Fasting is defined as no caloric intake for at least 8 h.

2-h PG uses a glucose load containing the equivalent of 75 g anhydrous glucose dissolved in water.

Management

The management plan should be formulated as an individualized therapeutic alliance among the patient and family, the physician, and other members of the health care team. Any plan should recognize diabetes self-management education as an integral component of care.

Glycemic control is fundamental to the management of diabetes and prevention of complications. While striving for glycemic control, the goals should be individualized with special considerations required in certain populations (children, pregnant women, and elderly). In patients with severe or frequent hypoglycemia, less intensive glycemic goals may be indicated. More stringent goals (i.e. a normal A1C, <6%) may further reduce complications at the cost of increased risk of hypoglycemia (particularly in those with type 1 diabetes). Recommended glycemic goals for nonpregnant adults and some important details of drugs used in diabetes are given in the appendix.

Other important aspects of management of diabetes include self-monitoring of blood glucose (SMBG), medical nutrition therapy (MNT), physical activity, prevention and management of complications and preventive care (e.g., pre-conception care, immunization etc).

Daily SMBG is especially important for patients treated with insulin to monitor for and prevent asymptomatic hypoglycemia (type 1 diabetes and other special situations like pregnant women taking insulin). HbA1C gives an idea regarding average glycemia over the preceding 2–3 months to assess treatment efficacy. Testing twice a year in patients, who are meeting treatment goals (and who have stable glycemic control) and quarterly in patients whose therapy has changed or who are not meeting glycemic goals, is recommended.

MNT is an integral component of diabetes management and self-management education. Goals are to attain and maintain recommended metabolic outcomes, to prevent and treat the chronic complications and comorbidities of diabetes, to improve health through healthy food choices and physical activity and to address individual nutritional needs while taking into consideration personal and cultural preferences and lifestyle. MNT should be individualized and preferably provided by a dietitian familiar with the components of diabetes MNT.

Regular exercise improves blood glucose control, reduces cardiovascular risk factors, contributes to weight loss, improves well-being in diabetes and can prevents type 2 diabetes in high-risk individuals. A baseline medical evaluation with appropriate diagnostic studies should screen for the presence of macro- and microvascular complications that may be worsened by the physical activity.

Prevention and management of diabetes complications: Though the management of most of the complications of diabetes requires specialized professional care, preventive measures and routine monitoring can be and should be an integral component of primary care. Criteria for monitoring and treatment of complications (e.g., cardiovascular including BP, lipids, antiplatelet measures, nephropathy, retinopathy, foot problems etc) are included in the appendix.

Nutritional Recommendations: Carbohydrate and monounsaturated fat together should provide 60–70% of energy intake. Less than 10% of energy intake should be derived from saturated fats. Those with LDL cholesterol >100 mg/dl may benefit from lowering saturated fat intake to <7% of energy intake and lowering dietary cholesterol to <200 mg/ day. For others, dietary cholesterol intake should be <300 mg/day. There is no need to modify protein intake if renal function is normal and no clear benefit from vitamin or mineral supplementation in the absence of deficiencies except folate for prevention of birth defects and calcium for prevention of bone disease.

PSYCHIATRIC ASPECTS OF DIABETES MELLITUS

Psychological characteristics of patients with diabetes

Role of life events and correlation of stressors with onset of diabetes, though proposed much earlier, has not yet been substantiated (Cobb and Rose, 1973). Claims regarding a diabetic personality (weakness, irritability, frequent mood swings, hypochondriasis, indecision, poor self reliance, vagueness about emotional feelings and problems in sexual identity) are mostly anecdotal (Menninger, 1935; Hinkle and Wolf, 1956) and do not have support from subsequent research (Wilkinson, 1981). According to a longitudinal cohort study in 105 type 2 diabetic patients in a clinical trial of a stress management intervention, lower average blood glucose values at baseline were associated with higher scores for the personality domain of neuroticism and several specific traits (including anxiety, hostility, depression, self-consciousness, and vulnerability) but with lower scores for the trait of altruism (Lane et al., 2000). In another study, predictors of metabolic control established (using the Dusseldorf Questionnaire for Narcissistic Regulation in Chronic Disease, DNACE) in the insulin treated group were low values in the scales "distrust", "feeling of being ashamed of disease", "feeling of inferiority" and "fighting self-image" and high values in the scales "value ideal" and "symbiotic protection of the self" (Kruse et al., 2000). The diagnosis of diabetes is a significant stressor for patients and also for their environment due to its attached stigma. Alterations are needed in several of their customary routines. The family's response to the diagnosis of diabetes may have a negative effect on glycemic control. Differences have been found in the way patients with type 1 diabetes and type 2 diabetes cope with and adapt to their diagnosis (Szydlo et al., 2003).

Cognitive dysfunction in diabetes

Potential for brain damage and cognitive dysfunction in diabetes arises from episodes of recurrent and severe hypoglycemia, metabolic complications like ketoacidosis and non-ketotic coma. Apart from some early studies with significant limitations showing decreased IQ in children and deficits in new word learning in adults with diabetes (Ack et al., 1961; Bale, 1973), the available literature is mostly on the effects of clinical and experimental hypoglycemic episodes on cognitive function. Chronic hyperglycemia and the production of advanced glycated end products may damage vascular tissue and endothelial function, increase free radicals, inflammatory responses, and amyloid deposition and may also influence cerebral blood flow, and neurotransmitter function. Diabetes could also influence cognitive function by leading to cardiovascular events, transient ischemic attacks, and strokes or by repeated hypoglycemic events and related metabolic and vascular disruption (Gregg and Brown, 2003). Several prospective studies have associated diabetes with cognitive decline and clinical dementia. However, randomized controlled trials demonstrating the benefit of glycemic control in preventing or reducing cognitive decline are needed.

Psychiatric disorders in diabetes mellitus

Prevalence of psychiatric disorders in diabetes mellitus has been studied using different methodologies. In a study comparing patients with chronic type 1 diabetes, their first-degree relatives and normal controls, prevalence of psychiatric disorders showed influence of gender. Lifetime and 6-month prevalence of simple phobia was more in female patients with diabetes compared to other two groups while in males, lifetime prevalence of antisocial personality disorder was more than in general population (Popkin et al., 1988). Lustman and colleagues (1986) found a 71% lifetime prevalence of at least one psychiatric disorder among 57 patients each of type 1 and type 2 diabetes. The commonest lifetime diagnoses were generalized anxiety disorder (41%) and major depressive disorder (33%), while 14% had current major depression. Except for simple phobias and agoraphobia (more in type 2), there was no significant difference in prevalence of psychiatric disorders between the two types of diabetes. Measure of HbA1 was significantly higher in ‘recently psychiatrically ill’ group when compared to ‘never ill’ group.

Adjustment disorders: Impact of adjustment disorders in those diagnosed with diabetes is most marked in case of children and adolescents with type 1 diabetes. But in addition to the stress of the diagnosis of a chronic debilitating illness imposing significant limitations on lifestyle and requiring frequent blood sugar monitoring and insulin injections, any specific biological factors underlie the comorbidity is less studied. School-age children with new-onset insulin-dependent diabetes mellitus were evaluated repeatedly and were diagnosed by using DSM-III. Of the 92 children, 33 developed adjustment disorder and five developed other psychiatric disorders in response to the diagnosis of insulin-dependent diabetes mellitus. Mean time from diabetes diagnosis to onset of adjustment disorder was 29 days, the average episode length was three months, and the recovery rate was 100% (Kovacs et al., 1995).

Depressive disorders: A recent meta-analysis (Anderson et al., 2001) reveals a mean prevalence of depressive disorder in patients with diabetes to be 14% (range 9%–27%) in studies using diagnostic interviews when compared to a higher prevalence of moderate to severe depressive symptoms (mean = 32%, range 22-60%) for studies utilizing self-report depressive symptom scales (Gavard et al 1993, Musselman et al., 2003). Diabetic patients at higher risk for depression have less education, are unmarried or have poor social support, and experience chronic stressors or negative life events (Peyrot and Rubin 1997; Fisher et al., 2001), while women with diabetes appear twice as likely to experience psychological distress as men (Lustman et al., 1986; Lustman et al 1988; Lloyd et al., 1992). Children with diabetes have a two-fold greater prevalence of depression, and adolescents up to three-fold greater, than youth without diabetes (Grey et al., 2002). In a controlled prospective study, among a group of 92 youths with type 1 diabetes, 24 developed major depressive disorder during a longitudinal follow-up of 10 years. When compared to patients who did not develop diabetes and a control group of 30 psychiatric patients with depression, diabetic subjects eventually spent more time being depressed. Young women with diabetes were at nine times greater risk for recurrent depression than their male counterparts (Kovacs et al., 1997). Increased levels of depressive symptoms are associated with decreased ability to adhere to a diabetic diet, poorer compliance with oral hypoglycemic medications (Ciechanowski et al., 2000), functional impairment and increased health care costs (Katon et al 1997; Ciechanowski et al., 2000; Egede et al., 2002). A recent meta-analysis of multiple cross-sectional studies (de Groot et al., 2001) showed that patients with diabetes and comorbid depression exhibit poorer glycemic control and greater prevalence of multiple diabetes complications (retinopathy, nephropathy, neuropathy, sexual dysfunction, and macrovascular complications).

Anxiety disorders: Reviewing 18 studies having a combined population of 4076 (2584 diabetic subjects, 1492 controls), the prevalence rates of various anxiety disorders were: generalized anxiety disorder (14%), anxiety disorder not otherwise specified (27%) and elevated anxiety symptoms (40%) in patients with diabetes. The prevalence of elevated symptoms was significantly higher in women compared to men and similar in patients with type 1 vs. type 2 diabetes (Grigsby et al., 2002). Anxiety is associated with poor glycemic control and treatment of anxiety is associated with improved glycemic control particularly in the subset of patients with more severe anxiety (Turkat, 1982; Lustman et al., 1995; Berlin et al., 1997). Patients of diabetes with high scores for the fear of blood and injury performed fewer blood glucose measurements and had poorer glycemic control (Berlin et al., 1997). Patients with blood-injection-injury phobia had higher than expected rates of macrovascular complications (Bienvenu and Eaton, 1998). These preliminary findings indicate the potential for improving compliance and long-term outcome in diabetes by proper management of comorbid phobic disorders.

Sexual dysfunction: Data on sexual dysfunction in diabetes is complex. Apart from the ‘organic’ erectile dysfunction (attributable to complications of diabetes like neuropathy and vascular disease), other aspects of sexual functioning like desire, arousal, ejaculation, orgasm and satisfaction are also impaired in patients with diabetes. Added to this are the comorbid psychiatric disorders (like depression, anxiety) and use of psychotropic medications, which significantly influence sexual function. In a study of psychological contributors or correlates of sexual dysfunction in diabetic men (in 40 diabetic men and 40 age-matched healthy volunteers), patients had significantly lower levels of erotic drive, sexual arousal, enjoyment and satisfaction which coexisted with alterations in sexual attitudes and body image (Schiavi et al., 1995). In a controlled study (35 type 1 diabetic married women with 42 healthy married controls, 23 type 2 diabetic women with 23 controls) on sexual function in females with diabetes, type 2 diabetes had a pervasively negative impact on sexual desire, orgasmic capacity, lubrication, sexual satisfaction, sexual activity, and on the relationship with the sexual partner, while type 1 diabetes was found to have little or no effect (Schreiner-Engel et al., 1987). Some others have investigated effects of sleep disorders in sexual function of patients with diabetes and found that respiratory abnormalities during sleep are associated with erectile difficulties in diabetic men (Schiavi et al., 1993). A recent review of randomized, placebo-controlled trials and retrospective analysis of data pooled from 10 clinical trials examined the efficacy of sildenafil citrate and found it efficacious as a first-line treatment for erectile dysfunction (in men with untreated minor depression, in men with erectile dysfunction that is refractory to successful SRI treatment of depression, and in those whose depression was successfully treated but who developed erectile dysfunction as a consequence of SRI treatment) (Nurnberg et al., 2002).

Eating disorders: A recent large multisite case-controlled study demonstrated that the prevalence rates of both full syndrome and subthreshold eating disorders among adolescent and young adult women with diabetes are twice as high as in their nondiabetic peers. Further, a 4-year follow-up study showed that disordered eating behavior in young women with diabetes often persists and is associated with a threefold increase in the risk of diabetic retinopathy. A brief psychoeducational intervention leads to a reduction in disturbed eating behavior but more intensive treatment approaches, may be needed to improve metabolic control (Rodin et al., 2002). Another study found that in women with type 2 diabetes, binge-eating frequency predicted blood glucose control after controlling for BMI and exercise level (Kenardy et al., 2001). In a cross-sectional study of 152 adolescents with type 1 diabetes, female patients aged 13-14 years were at greatest risk for developing disordered eating patterns. Longer duration of disease, more symptoms of bulimia, and obesity all predicted poorer glycemic control (Meltzer et al., 2001). After approximately 10 years of follow-up of 510 females with type 1 diabetes, 658 females with anorexia nervosa and 23 concurrent cases, mortality rates (per 1,000 person-years), crude mortality rates and standardized mortality ratio were significantly higher for the concurrent cases (Nielsen et al., 2002). Patients with both diabetes and eating disorders had significantly higher levels of comorbid anxiety, panic attacks, and alcohol use disorders, compared with those with one but not both (Goodwin et al., 2003).

Factitious disorders: Factitious hypoglycemia as a manifestation of Munchausen’s syndrome, was assessed in a study which detected a second generation of the sulfonylurea oral hypoglycemic agent in 17% of 129 patients who had unexplained severe hypoglycemia (Trenque et al., 2001). Similar situations relevant to diabetes treatment wherein patients present with hypoglycemic episodes (by voluntary overdosage of hypoglycemic drugs) or ketoacidosis (skipping insulin doses) have been reported.
 

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