Читать книгу Clinical Dilemmas in Diabetes - Группа авторов - Страница 56

It is important to appreciate that the classification of type 1 and type 2 diabetes was originally somewhat arbitrary and has now evolved into a “positive” diagnosis of type 1 diabetes – based on the presence of autoantibodies – and a diagnosis of type 2 diabetes “by exclusion” i.e. no evidence of islet autoimmunity. However, this approach has significant limitations driven in part by the nature of the tests used and by the heterogeneity of type 2 diabetes [1]. Of course, the ultimate demonstration of an immune‐mediated cause of diabetes would require documenting an immune infiltrate within islets [2]. This is extremely invasive, has a significant risk of serious complications and for these reasons is almost never undertaken (nor should it).

Several authors have argued persuasively that if the ultimate goal of diabetes management is to achieve glycemic control safely and effectively, then the underlying diagnosis may be less important [1]. In the absence of therapeutic choices this may be less important but given the proliferation of therapeutic classes in diabetes pharmacotherapy a greater understanding of the pathophysiologic abnormalities resulting in hyperglycemia may help optimize therapy. This is perhaps best illustrated by the demonstration that several forms of monogenic diabetes respond to sulfonylureas and do not necessarily need insulin therapy [3]. Early detection and treatment of hemochromatosis may prevent loss of pancreatic islet function and diabetes associated with generalized lipodystrophy responding to leptin therapy serve as other examples.

How does hyperglycemia arise? In the postprandial state glucose concentrations are the net result of stimulation of insulin secretion, suppression of glucagon secretion, the ability of insulin (insulin action) and glucose (glucose effectiveness) to suppress endogenous glucose production and stimulate glucose uptake by the tissues, and the rate of gastric emptying. In type 1 diabetes, all defects are ultimately secondary to insulin deficiency whereas in type 2 diabetes the relative contribution of these parameters is more variable [4, 5].

Defective and/or delayed insulin secretion is the hallmark of all forms of diabetes and the presence of hyperglycemia implies that the degree of insulin secretion is inadequate for the prevailing insulin action [6]. Increasing secretory demands may overwhelm the ability of β‐cells to assemble insulin leading to protein misfolding and a cascade of mechanisms, including the unfolded protein response, that result in dysfunction and if unchecked the death of the β‐cell [7, 8]. Common genetic variation associated with type 2 diabetes has helped to identify multiple pathways associated with the synthesis and secretion of insulin. It is important to note, however, that the genetic predisposition to fasting hyperglycemia differs from that predisposing to glucose intolerance [9, 10]. This is concordant with the observation that impaired fasting glucose can occur independently of impaired glucose tolerance and vice‐versa in prediabetes [11].

Abnormalities of glucagon suppression are observed in both type 1 and type 2 diabetes and were initially attributed to insulin deficiency within the islet [12]. However, insulin restraint of α‐cell secretion may not be as important as previously thought [13, 14]. Certainly there are other paracrine regulators of glucagon secretion [15]. Abnormal glucagon secretion arises early in prediabetes and occurs independently of defects in insulin secretion [14]. Underlining its importance in the pathogenesis of diabetes is the observation that people with diabetes‐associated genetic variation exhibit defects of α‐cell function [16, 17].

The factors altering the ability of insulin and of glucose itself to suppress endogenous glucose production (and release into the circulation) as well as stimulate uptake are less well understood although weight, adiposity and physical activity all influence these parameters. Genetic predisposition to defects in insulin action, for example, is less well characterized. Certain syndromes such as polycystic ovarian syndrome are associated with diabetes through effects on insulin resistance [18, 19].

The final variable affecting glycemic control is upper gastrointestinal function. The stomach and proximal small bowel function in unison to dampen fluctuations in the rate of appearance of ingested calories into the duodenum and jejunum after meals. Multiple neural and hormonal inputs regulate gastric volume and wall tension (allowing accommodation of ingested food), pyloric tone and the rate of gastric emptying [20]. Although this integrated system regulates satiety and, to a lesser extent, caloric intake, there has been no clear association with predisposition to diabetes. For example, most of the benefits of bariatric surgery occur through changes in caloric intake and weight loss [21] and are likely independent of the rate of gastric emptying – outcomes after sleeve gastrectomy and Roux‐en‐Y‐Gastric Bypass (RYGB) are broadly comparable – despite a far higher rate of gastric (pouch) emptying after RYGB [22].