Insulin – Pharmacology, Types of Regimens, and Adjustments

With the introduction of several new insulins since 1996, insulin therapy options for type 1 and type 2 diabetics have expanded.  Insulin therapies are now able to more closely mimic physiologic insulin secretion and thus achieve better glycemic control in patients with diabetes.  This chapter reviews the pharmacology of insulins (using a comparative approach), types of insulin regimens and therapeutic adjustment of them, and provides an overview of insulin pump therapy.

Insulin signaling and action: glucose, lipids, protein

Diabetes is a chronic metabolic disorder affecting ~ 5% of the population in industrialized nations. Lack of or severe reduction in insulin secretion due to autoimmune destruction of β cells is responsible for type 1 diabetes mellitus. The more prevalent form, type 2 diabetes, accounts for more than 90% of cases. The pathogenesis of type 2 diabetes is complex, involving progressive development of insulin resistance and a relative deficiency in insulin secretion, leading to overt hyperglycemia [1][2].

Inflammation and insulin resistance

The hypothesis that inflammation in metabolic tissues may contribute to the development of insulin resistance originated from a discovery in 1993 when it was found that TNFa, an inflammatory cytokine, causes insulin resistance [182]. Subsequently, additional inflammatory cytokines as well as downstream mediators of these cytokines are also shown be a cause of obesity-induced insulin resistance [183]. A source of these inflammatory cytokines appears to be adipose macrophages, infiltration of which is a common observation in obesity. In parallel, fatty acids, readily derived from ingested nutrients, activate Toll-like receptor 4, a mediator of NF-kB pathway that directly antaogonize the actions of insulin in metabolic tissues [184]. The adipose tissue is thus dually regulated by both nutritional stimuli (e.g., fatty acid) as well as inflammatory cytokines (e.g., TNF-a). This hypothesis is strengthened by the recent finding that the six-transmembrane protein STAMP2 responds to both nutrients and inflammatory cytokines. STAMP2, which is preferentially expressed by adipose tissue, counteracts obesity-induced insulin resistance by antagonizing the actions of excess nutrients and inflammatory cytokines [185].

Adipose-secreted proteins

Adipose tissue is now recognized as an active endocrine organ that secrets a variety of hormones that regulate cellular processes. As discussed above, elevated TNF-α expression has been observed in adipose tissue derived from obese animal models and human subjects. TNF-α has also been implicated as a causative factor in the development of insulin resistance associated with obesity and diabetes [186][187][188][189]. Treatment of cells with TNF-α produces impaired insulin signaling through IRS-1 serine phosphorylation [190][191] or through reduced expression of IRS-1 and GLUT4 [192]. TNF-α suppresses adipocyte differentiation and expression of adipocyte-specific genes in vitro [193]. Peroxisome proliferator-activated receptor (PPAR)γ is an adipocyte-specific nuclear hormone receptor that functions as a key transcriptional regulator of adipogenesis. Agonists of PPARγ such as TZDs (e.g., troglitazone, pioglitazone, and rosiglitazone) promote adipocyte differentiation and improve insulin sensitivity in animal models of obesity and diabetes as well as in type 2 diabetic patients [194]. TNF-α and PPARγ signaling pathways are mutually antagonistic and activation of PPARγ can attenuate the negative metabolic effects of TNF-α in cells and in vivo [195][196][197].

Leptin belongs to the cytokine family of hormones and is secreted by adipose tissue. Leptin exerts it effect by interacting with its receptors in the central nervous system and periphery [198]. Severe leptin deficiency or leptin signaling deficiency is associated with insulin resistance as manifested in db/db, ob/ob mice, Zucker fatty rats, or animal models of genetic lipodystrophic diabetes [199]. In addition to its effect on satiety and body weight, leptin can also modulate insulin action in liver and muscle [200][201][202]. Leptin replacement in human subjects with lipodystrophy and leptin deficiency leads to improved glycemia control and decreased lipid levels [203].


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