Hyperglycemia, for better or for worse [1], is the metabolic abnormality that has been used to define the presence of, and characterize, diabetes. Diabetes comprises a heterogeneous group of disorders characterized by fasting and/or post-prandial hyperglycemia. The underlying abnormalities that lead to the development of hyperglycemia, however, differ amongst subgroups. Conventionally, diabetes has been categorized into two subgroups that, from a metabolic standpoint, differ in the degree of insulin deficiency present. This broad dichotomy is simplistic as a given patient may exhibit metabolic abnormalities previously considered unique to each category [2].

Type 1 (T1DM), or immune-mediated diabetes, is characterized by evidence of immune-mediated destruction of the insulin-secreting β-cells in the islets of Langerhans. Usually this leads to absolute insulin deficiency, which is insufficient to prevent unrestrained lipolysis during systemic illness or severe physical stress. In type 2 diabetes (T2DM), however, although the endocrine pancreas can produce insulin, secretion and circulating concentrations of insulin are inappropriate for the prevailing glucose concentrations. T2DM has traditionally been considered a disorder of insulin signaling (exacerbated by poor diet, obesity and lack of physical activity) rather than a deficiency of insulin.

It is important to remember that obese patients with T1DM can behave in a fashion similar to patients with long-standing T2DM and that metabolic differences between the two categories may be more imagined than real.

In the fasting state, glucose appearance is determined by the rate of endogenous glucose release from the liver and to a lesser extent the kidney. This is collectively referred to as endogenous glucose production. Glucose concentrations increase when glucose appearance exceeds glucose disappearance and continues to increase until these rates are equal. In humans without diabetes, glucose concentrations average 4.5–5.5 mmol/L following a 6–12-hour overnight fast.

Gluconeogenesis is responsible for approximately 50–60% of endogenous glucose production following an overnight fast, with the proportion increasing with increasing duration of the fast [3]. Gluconeogenesis utilizes three-carbon precursors such as lactate, alanine and glycerol to synthesize glucose molecules.

Following an overnight fast, approximately 80% of glucose disposal is insulin independent and occurs in the brain, splanchnic tissues and erythrocytes [4]. The majority of insulin-mediated glucose disposal occurs in muscle [5]. Because insulin levels are low in the post-absorptive state, muscle predominantly uses free fatty acids (FFA) for fuel [6]. In the presence of low insulin concentrations, glucose taken up by tissues predominantly is oxidized or undergoes glycolysis to release alanine and lactate which can be re-utilized by the liver for gluconeogenesis [7].

T1DM is characterized by insulin deficiency as a result of autoimmune destruction of the pancreatic β-cells. Fasting hyperglycemia does not develop until most (>80%) of β-cells are lost to the underlying autoimmune process. Defects in insulin secretion, however, are evident years before the development of diabetes in asymptomatic affected individuals. For example, siblings of people with T1DM who are islet antibody positive (a group at high risk for the development of T1DM) frequently exhibit a decreased first-phase of insulin secretion in response to intravenous glucose injection [25,26]. This usually occurs at a time when the response to other stimuli such as oral glucose or mixed meal ingestion is intact, suggesting that incretins and other secretagogues are capable of compensating for decreased islet cell mass.

Impaired insulin secretion is frequently accompanied by impaired insulin action [27,28]. The severity of insulin resistance is related to the degree of glycemic control. People with poorly controlled T1DM may exhibit the same degree of insulin resistance as people with T2DM [28,29]. In people with T1DM, the defect in insulin action is tissue-specific; for example, glucose uptake in cardiac muscle, as opposed to skeletal muscle, is normal [30]. Glucose oxidation and non-oxidative storage in people with T1DM is decreased in proportion to glucose uptake, suggesting that glucose transport and/or phosphorylation (after transport across the membrane) are the sites of defective insulin action [31]. In contrast, insulin-induced suppression of glucose production is not impaired and may in fact be increased in people with T1DM [32,33].

Insulin binding and action has been reported to be decreased in adipocytes [34,35] but normal in fibroblasts [36,37] of people with T1DM. This may be explained by the fact that insulin binding in adipocytes is measured immediately after biopsy while insulin binding to fibroblasts is measured following several days of culture. Decreased insulin binding in the former but not the latter suggests an effect of abnormal metabolic milieu rather than an intrinsic defect of insulin action. This is supported by several observations that improved chronic glycemic control is accompanied by improved whole-body insulin action [38,39]. It should be noted that when insulin action is measured by means of a hyperglycemic hyperinsulinemic clamp, hyperglycemia may compensate for small defects in insulin action by means of its ability (glucose) to stimulate its own uptake and suppress its own release (glucose effectiveness) [33].

Because insulin is typically delivered via the subcutaneous, rather than the intraportal route, treatment with insulin leads to systemic hyperinsulinemia which has been shown to impair insulin action in humans without diabetes [40]. The improved insulin action observed in people with T1DM following treatment with insulin, however, suggests that any negative effects of systemic hyperinsulinemia on insulin action are more than offset by the lowering of glucose concentrations and the reversal of glucose toxicity.

In the absence of insulin-stimulated muscle glucose uptake, substantial glucose disappearance in insulin-deficient people with T1DM occurs by glucose excretion in the urine and by glucose uptake via non-insulin-mediated pathways [41]. Food ingestion does not result in a rise in insulin or a reciprocal decrease in glucagon concentration [42]. Because of this, the increase in splanchnic glucose uptake and the decrease in endogenous glucose production are not appropriate for the prevailing glucose concentration. Post-prandial glycogen synthesis is markedly decreased, with most of the glycogen being synthesized by the indirect gluconeogenic pathway [43,44].

Consequently, because of abnormal hepatic glucose handling, excessive amounts of glucose reach the systemic circulation. The excessive rise in post-prandial glucose concentrations is compounded by the low insulin concentrations and defective insulin action present in people with poorly controlled T1DM [41,45]. In contrast, the ability of glucose to stimulate its own uptake and suppress its own release (glucose effectiveness) is normal in T1DM and most post-prandial glucose disposal occurs predominantly via non-insulin mediated pathways and by glucose excretion in the urine [46].

Post-prandial glucose metabolism in the splanchnic and extra-splanchnic tissues can be almost completely normalized by insulin administration which increases circulating insulin concentrations and prevents the excessive rise in counter-regulatory hormones that accompanies insulin deficiency. Insulin administration also restores post-prandial suppression of glucose production and stimulation of glucose uptake to rates similar to those observed in subjects without diabetes [41,47].

People with T2DM have elevated fasting glucose levels and excessive glycemic excursions following carbohydrate ingestion. Insulin secretion in those with T2DM is typically decreased and delayed following food ingestion [9,21]. Defects in insulin secretion are observed early in the evolution of T2DM. In fact, alterations in both the timing and amount of insulin secreted have been reported in relatives of patients with T2DM prior to the development of hyperglycemia [50,51].

Chronic hyperglycemia alone or in combination with elevated FFA impairs insulin secretion. Abnormalities in glucose sensing, insulin processing or intracellular signaling can alter insulin secretion [52]. In addition, β-cell mass decreases with increasing duration of diabetes [53,54]. Alterations in β- cell morphology occur in most people with T2DM with extensive intra-islet deposition of amylin commonly being observed [55,56].

Prolonged elevations in glucose concentration following ingestion of a carbohydrate-containing meal occur because post-prandial glucose appearance exceeds disappearance. The more significant the defects in insulin secretion and action, the higher glucose concentrations have to rise to balance glucose appearance and disappearance [57]. Glucose appearance is elevated because of failure to suppress hepatic glucose production because the systemic rate of appearance of ingested glucose does not differ from that observed in individuals without diabetes [9,11,17,58]. Although glucose disappearance is commonly higher in people with diabetes than in individuals without diabetes following a meal, this is in large part is accounted for by elevated rates of urinary glucose excretion. Furthermore, although elevated, the rates of glucose disappearance are not appropriate for the prevailing glucose concentrations [59,60].

Defects in insulin secretion and action both contribute to post-prandial hyperglycemia. A delay in the early rise in insulin concentrations causes a delay in suppression of glucose production, which in turn results in an excessive glycemic excursion. In contrast, a decrease in insulin action results in sustained hyperglycemia but has minimal effect of peak glucose concentrations. Whereas an isolated alteration in either hepatic or extrahepatic insulin action impairs glucose tolerance, a defect in both results in severe hyperglycemia [57].

Glucose is also an important regulator of its own metabolism. In the presence of basal insulin concentrations, an increase in plasma glucose stimulates glucose uptake and suppresses glucose production. The ability of glucose to regulate its own metabolism is impaired in T2DM. This is commonly referred to as a defect in “glucose effectiveness.” Whereas intravenous infusion of 35 g glucose in individuals without diabetes whose insulin concentrations are clamped at basal levels produces only a modest rise in plasma glucose concentration, infusion of the same amount of glucose results in severe hyperglycemia in people with T2DM [61]. The excessive rise in glucose is caused by impaired glucose induced stimulation of glucose uptake because glucose induced suppression of glucose production is normal [61,62].