The interaction of insulin resistance and Bcell function

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Having presented the major aspects of insulin secretion and IR, some examples of DM and its related disorders according to their main determinant are now discussed: predominantly insulin deficiency, predominantly IR, or resulting from relative insulin deficiency in the context of IR.

Diabetes with predominantly insulin deficiency

Type 1 diabetes

Type 1 diabetes is the form of the disease caused primarily by ( -cell destruction. This condition is characterized by severe insulin deficiency and dependence on exogenous insulin to prevent ketosis and to preserve life; it was called insulin-dependent DM. The natural history of this disease indicates that there are preketotic, non-insulin-dependent phases both before and after the initial diagnosis. Although the onset is predominantly in childhood, the disease may occur at any age.

It is possible that nonautoimmune and autoimmune destruction of ( -cells could coexist, but the current classification considers two subtypes. In type 1a there is evidence suggesting an autoimmune origin of ( -cell destruction, mostly determined by the presence of circulating antibodies against islet cells; insulin antibodies in the absence of exposure to exogenous insulin; or antibodies to glutamic acid decarboxylase, and/or islet cell-associated phosphatase. This autoimmune entity also is associated with certain HLAs. Patients with type 1a are also more likely to have other concomitant autoimmune disorders, such as autoimmune thyroiditis, Addison's disease, and celiac disease.

The type 1b form of diabetes is characterized by low insulin and C peptide levels similar to those in type 1a, although there is no evidence of an autoimmune etiology of the ( -cell destruction. As in autoimmune diabetes, patients are prone to ketoacidosis. This idiopathic diabetes reflects the still limited knowledge of the etiology of many forms of diabetes.

Maturity-onset diabetes of the young

Maturity-onset diabetes of the young comprises a heterogeneous group of disorders of monogenic defects in ( -cell function. It is believed that a more appropriate term for this group is monogenic diabetes of the young. The maturity-onset diabetes of the young syndromes are characterized by dominant inheritance with at least two and preferably three consecutive generations, and onset before age 25 to 30 years. The first maturity-onset diabetes of the young gene was found in 1992 [45], and since then six forms of maturity-onset diabetes of the young syndromes have been described (see also the article by Nakhla and Poly-chronakos elsewhere in this issue).

Mitochondrial diabetes

Mitochondrial diabetes, also called maternally inherited diabetes and deafness, is characterized by a progressive decline in ( -cell function. Cases of mitochondrial diabetes are often misdiagnosed as type 1 or type 2 diabetes depending on degree and age of progression of the insulinopenia. The diagnosis should be suspected when there is a marked history of diabetes associated with bilateral deafness in most carriers that follows a maternal inheritance. The most common mutation associated with this type of diabetes is the A3243G mutation in the mitochondrial DNA-encoded tRNA. The molecular mechanism by which the A3243G mutation affects insulin secretion may involve an attenuation of cytosolic ADP-ATP levels causing the resetting of the glucose sensor in the pancreatic (-cell [46]. The A3243G mutation is present in heteroplasmic form (the patient carries a mixture of normal and mutant mitochondria) and there is a trend toward a lower age of onset at high heteroplasmy values [47].

Hearing impairment generally precedes the onset of clinically manifest diabetes by several years and changes in pigmentation of the retina are also present in many carriers of the A3243G mutation [46]. Patients with mitochondrial diabetes show a pronounced age-dependent deterioration of pancreatic function with a mean age of presentation of 38 years [46]. The same mitochondrial variant is found in the MELAS syndrome (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like syndrome), although diabetes in not part of this syndrome [48].

Diabetes and other syndromes with predominantly insulin resistance

A number of mutations of the insulin receptor resulting in diabetes have been identified. Although these are rare causes of diabetes they should be considered in a patient with marked features of IR and exceptionally high insulin levels. These mutations lead to at least three clinical syndromes, all of them characterized by findings secondary to IR (Table 4) [49].

Lipoatrophic diabetes

Lipoatrophic diabetes presents with paucity of fat, IR, and hypertriglycer-idemia. There are several forms, including face-sparing partial lipoatrophy (the Dunnigan syndrome or the Koberling-Dunnigan syndrome), an autosomal-dominant form caused by mutations in the lamin A/C gene, and congenital generalized lipoatrophy (the Seip-Berardinelli syndrome), an autosomal-recessive form [50].

Metabolic syndrome

The metabolic syndrome, also called the IR syndrome, has become the major health problem of this time. This clinical phenotype is characterized by abdomi-

Table 4

Insulin receptor mutation syndromes

Syndrome Clinical characteristics

Type A insulin resistance Insulin resistance, acanthosis nigricans, and hyperandxogenism

Leprechaunism Multiple abnormalities, including intrauterine growth retardation, fasting hypoglycemia, and death within the first 1 to 2 years of life

Rabson-Mendenhall syndrome Short stature, protuberant abdomen, and abnormalities of teeth and nails nal obesity, dyslipidemia, elevated blood pressure, IR, and a proinflammatory state and is one of the major risk factors for cardiovascular disease [51,52]. Although some single-gene defects affecting satiety or energy homeostasis have been shown to produce this syndrome, in most cases it is the consequence of the interaction of multiple genes with lifestyle factors of excessive carbohydrate and fat consumption and lack of exercise. IR as an integral part of the syndrome is likely both the cause and consequence of many of the metabolic alterations seen in this syndrome. It is not surprising that the metabolic syndrome is a risk factor for type 2 diabetes, because adding (-cell failure to the prevailing IR leads to loss of glucose homeostasis.

Polycystic ovary syndrome

Polycystic ovarian syndrome is a reproductive disorder characterized by hyperandrogenism and chronic anovulation not caused by specific diseases of the ovaries, adrenals, and pituitary. It is one of the most common hormonal disorders in women, with a prevalence estimated between 5% and 10% [53-55].

Women with the polycystic ovary syndrome are more insulin resistant than are controls [56]. In these women, insulin acts synergistically with luteinizing hormone to increase the androgen production by ovarian theca cells. Insulin also inhibits hepatic synthesis of sex hormone-binding globulin, the main carrier protein for testosterone, and increases the proportion of testosterone that circulates in the unbound, biologically available, or free, state.

The sole presence of IR does not lead to diabetes and 30% to 40% of women with the polycystic ovary syndrome have impaired glucose tolerance, and as many as 10% have type 2 diabetes by their fourth decade [57,58]. This implies that most women with polycystic ovarian syndrome are able to compensate for their degree of IR and those whose (-cell function is abnormal or deteriorates progress to diabetes.

Diabetes resulting from combined insulin deficiency and insulin resistance

Type 2 diabetes mellitus

Type 2 DM is the most common form of diabetes in adults, and its prevalence in children is increasing. It is characterized by IR and defective insulin secretion, either of which can be the predominant feature. Patients with type 2 DM usually have IR and relative rather than absolute insulin deficiency. Pediatric patients with type 2 DM are likely to be overweight or obese and present with glycosuria without ketonuria, absent or mild polyuria and polydipsia, and little or no weight loss. Up to 33% have ketonuria at diagnosis, and 5% to 25% of patients who are subsequently classified as having type 2 diabetes have ketoacidosis at presentation. Children with type 2 diabetes usually have the metabolic syndrome, have a family history of type 2 diabetes, and are more likely to be of non-European ancestry (African, Hispanic, Asian, and American Indian descent) [59]. Type 2 DM patients are most likely antibody negative, although in adults a syndrome of clinical type 2 diabetes with positive autoantibodies has been de scribed as latent autoimmune diabetes [60]. Acanthosis nigricans and polycystic ovarian syndrome, disorders associated with IR and obesity, are common in youth with type 2 diabetes.

Currently, children with type 2 diabetes are usually diagnosed over the age of 10 years and are in middle to late puberty. With increased obesity and IR in the population, more and younger individuals with poor (3-cell function develop diabetes.

Longitudinal studies examining the progression from normal glucose tolerance to impaired glucose tolerance in Pima Indians have demonstrated that the transition from normal glucose tolerance to impaired glucose tolerance was associated with an increase in body weight, a modest increase in IR, and a significantly greater decline in insulin secretion when measured by the first-phase insulin response to intravenous glucose [61].

Cystic fibrosis-related diabetes

About 5% to 10% of patients with cystic fibrosis have diabetes based on fasting glucose levels, but the prevalence of glucose homeostasis abnormalities has been described in up to 34% [62,63]. The clinical course of these patients is characterized by a slow progression from normal glucose tolerance to impaired glucose tolerance and ultimately fasting hyperglycemia [62,63], with no tendency to ketosis. Patients frequently become glucose intolerant at times of illness. This is presumably caused by limited insulin secretion, which cannot compensate for the stress-induced resistance to insulin action. One such ''stress'' is the use of glucocorticoid bursts to dampen pulmonary inflammation. Poor ( -cell function seems to be the major contributor to cystic fibrosis-related diabetes. In comparison with controls, normal glucose-tolerant cystic fibrosis patients have higher glucose levels at 30, 60, and 90 minutes associated with a delayed rise in insulin levels [64-67] and a decreased first-phase insulin release [68]. It is possible that the alteration in ( -cell function may be caused by altered function of the cystic fibrosis transmembrane conductance regulator because it is expressed in pancreatic islets [69]. Although there are conflicting reports on the involvement of IR in cystic fibrosis-related diabetes [70-77], the trend of worsening in glucose tolerance with ageing and exacerbations of pulmonary disease is suggestive of an episodic worsening of IR. Increased inflammatory milieu or medications (ie, steroids) are likely to explain a significant part of the increase in IR.

Cystic fibrosis-related diabetes is a good example of the balance of insulin secretion and IR. Most patients have enough ( -cell function to maintain normo-glycemia, and this balance is lost in periods of increased IR.

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