Insulin Secretion
Instead of postulating insulin resistance and peripheral underutilization of glucose as the primary defect, some investigators have proposed that impaired insulin secretion and impaired suppression of hepatic glucose production are the important determinants of glucose intolerance [102,113]. Gerich [114] based his view on the evaluation of insulin secretion after an oral glucose load. In subjects with impaired glucose tolerance, and even more in those with clinical N1DDM, early insulin secretion is reduced and late insulin secretion increased [115]. Defective early insulin release is responsible for impaired glucose tolerance, which on its part triggers late hyperinsulinemia. The suppression of hepatic glucose production is impaired [102,116], resulting in increased hepatic glucose output. Under steady-state conditions this is equal to increased glucose disposal. Indeed, forearm muscle glucose uptake is not impaired in person with impaired glucose tolerance [116]. From these observations, Gerich concluded that peripheral insulin resistance cannot be an important pathogenetic factor [114].
Hepatic glucose output is directly related to fasting plasma glucose, supporting the view that the liver plays a major role in fasting hyperglycemia. However, increased hepatic glucose output may not be a primary defect. As mentioned before, increased hepatic glucose output can be explained as a response to enhanced lipolysis, with the primary defect being ascribed to insulin resistance of the adipocyte.
Recently, in order to elucidate the sequence of events, body weight and body composition, insulin secretion, insulin action, and endogenous glucose output were continuously monitored in a longitudinal study over several years in Pima Indians in whom normal glucose tolerance progressed to diabetes [117]. Progression to impaired glucose tolerance was associated with an increase in body weight and fat mass and a decline in both early insulin response to a glucose stimulus and insulin-stimulated glucose disposal. Progression to diabetes was accompanied by progression of these two disorders and, in addition, by an increase in basal endogenous glucose output. Subjects who retained a normal glucose tolerance in spite of weight gain (nonprogressors) were insulin-resistant but improved their early insulin secretion. According to this study, the ability to improve early insulin secretion decides progression to diabetes. Increased endogenous glucose output is a later event in the development of type 2 diabetes [117].
Genes responsible for defects of early insulin secretion and insulin secretory capacity have not yet been identified. However, the familial nature of type 2 diabetes leaves little doubt that they play a role. On the other hand, secretory defects may also be acquired due to glucose toxicity or hyperlipacidemia [118]. Thus, there is evidence for primary genetic and secondary environmental influences on insulin secretion and insulin sensitivity, respectively.
Clinical Picture of Diabetes Mellitus
Acute Symptoms
Mild hyperglycemia usually does not cause symptoms and may not be noticed by the patient, but severe hyperglycemia will always cause clinical symptoms.
People with untreated diabetes develop progressive hyperglycemia. When the renal threshold for plasma glucose of about 7 mmol/l is surpassed, glucose is excreted with the urine. Glucosuria goes along with osmotic diuresis and results in large urine volume, thirst, exsiccosis, and electrolyte disorders. Together with these effects of insulin deficiency, electrolyte imbalance is accentuated by cellular loss and renal excretion of potassium. Protein synthesis is lowered and accelerated proteolysis results in protein loss from muscle and other tissues. Increased amino acid levels in blood may be utilized for energy metabolism and gluconeogenesis. Lipid storage is blocked, while lipolysis is increased. This results in the massive appearance of FFA in blood. They are in part incorporated into lipoproteins, thus inducing hyper- and dyslipidemia. FFA also swamp into the energy metabolism. This process is enhanced by elevated levels of plasma glucagon, which activates the enzyme carnitine-palmitoyltransferase (CPT-1) and the transport of long-chain fatty acids into the mitochondria. Here they compete with glucose for the oxidative chain, thus decreasing glucose oxidation. The supply of FFA is greater than the energy need. The FFA surplus is only degraded to the level of β-hydroxybutyrate and α-ketoglutarate, which may accumulate and cause ketoacidosis.
FFA also stimulate gluconeogenesis and hepatic glucose output, they modulate signal chains (e.g., PI-3 and IRS phosphorylation depressed. PKC activated), and contribute to metabolic insulin resistance (pages 6–8).
These disorders result in the classical symptoms of insulin deficiency: polyuria, thirst, polydipsia, exsiccosis, muscle wasting, loss of lipid stores, weight loss, polyphagia, fatigue, and nausea. At diagnosis, about 1% of the subjects have developed ketoacidosis with hyperventilation and eventual coma.
Type 1 Diabetes
Five phases of type 1 diabetes mellitus may be distinguished.
Prediabetes is characterized by the presence of islet cell autoantibodies in blood serum without metabolic disorders. Clinically important types are antibodies against islet cell cytoplasm (ICA), glutamic acid decarboxylase(LGAD), and tyrosinphosphatase (IA-2) (Table 1.10). Islet cell autoantibodies can often be detected many years before clinical manifestation. Transient presence of antibodies may have no relevance, but persisting antibodies indicate that type 1 diabetes will follow with a probability that increases if more than one autoantibody is detected and if they are present at high titers. In antibody-positive persons they should be monitored once or twice per year. Tests for insulin secretory capacity may have additional predictive value [44].
At manifestation symptoms are more frequent in younger than in older individuals. In young subjects it may be only hours or a few days from the first signs until a serious clinical syndrome develops. In later adulthood, the progression from insulin deficiency to overt clinical diabetes is often retarded [120–122]. The clinical picture of these people may resemble that of type 2 diabetes, but they are islet cell antibody-positive and will usually need insulin during the first year after diagnosis. It can be expected that about 10% of newly diagnosed diabetic subjects originally classified as having type 2 in fact have this form of type 1 diabetes [12]. The term “latent autoimmune diabetes inadults” (LADA) has been used to describe this subgroup.
Table 1.10 Islet cell specific autoantibodies in type 1 diabetes. Prevalence at manifestation
| Antibodies
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