Insulin group

Of 335 patients with type 1 diabetes randomized to receive preprandial inhaled insulin as a dry powder formulation via an aerosol delivery system (Exubera) plus bedtime subcutaneous Ultralente insulin, or to continue NPH and regular insulins subcutaneously, 170 received inhaled insulin (mean age 33 years) (272). Six discontinued inhaled insulin, one because of mild cough, two because of hypoglycemia, and three because of insufficient responses. The risk of hypoglycemia was slightly lower in those who used inhaled insulin, at 8.6 events per month compared with 9.0 events per month in the conventional insulin group. 

Fig. 9.6 (A) Hemoglobin A1 c (HbAlc) levels in the inhaled and subcutaneous (SC) insulin groups. (B) Mean change in fasting plasma glucose concentration in the inhaled and SC insulin groups. (Reproduced with permission from [60]).

In another study exubera was used in monotherapy or added to dual oral agent therapy in type 2 patients with an HbAlc between 8% and 11% [59]. The study design was a 12-week open label randomised trial. Exubera was used as a premeal insulin in the two insulin arms with either dual oral agents or as monotherapy. In the third treatment arm patients continued receiving dual oral agents [59]. At week 12 both inhaled insulin groups had a... 

In a 6-month study type 2 diabetic patients were randomised to treatment with premeal inhaled insulin plus bedtime ultralente or at least two injections of subcutaneous insulin (premix human/NPH insulin) [60], HbAlc decreased similarly in both groups (0.7% vs. 0.6%), and no difference was found in the number of hypoglycaemic events. Insulin-binding antibodies increased more in the inhaled insulin group [60]. 

In the study by DeFronzo and coworkers, inhaled insulin was compared with rosiglitazone in 150 patients with suboptimal control on diet and exercise (HbAlc 9.4%) [61]. The HbAlc reduction was greater in the inhaled insulin group (2.3%) compared with 1.4% in the rosiglitazone group. 

Lastly, Barnett et al. in a 24-week study randomised type 2 patients uncontrolled on sulfonylurea monotherapy to inhaled insulin before meals or metformin and demonstrated in subjects with HbAlc >9.5% at randomisation a greater reduction in HbAlc in the inhaled insulin-treated group (2.2% vs. 1.8%) [62]. In the patients with HbAlc <9.5% at randomisation, the decrease in HbAlc was not different between the two groups. More events of hypoglycaemia were observed in the inhaled insulin group [62]. 

Plate 54. The insulin group of Helmut Zahn (Photo M. Forschelen, Aachen) from left H. Bremer, O. Brinkhoff, H. Zahn, R. Zabel, E. Schnabel, J. Meienhofer... 

In a 52-week study, 336 patients, mean age 56 years, with type 2 diabetes were randomized to inhaled insulin (Technosphere, MannKind, Valencia, USA) in combination with insulin glargine and compared with 343 patients taking biaspart insulin 107 patients withdrew in the inhaled insulin group and 85 in the biaspart group [14 =]. This was in part due to a greater number of adverse events. Cough and upper respiratory tract infections were more common in those who used inhaled insulin. 

Disulfides. As shown in Figure 4, the and h-chains of insulin are connected by two disulfide bridges and there is an intrachain cycHc disulfide link on the -chain (see Insulin and other antidiabetic drugs). Vasopressin [9034-50-8] and oxytocin [50-56-6] also contain disulfide links (48). Oxidation of thiols to disulfides and reduction of the latter back to thiols are quite common and important in biological systems, eg, cysteine to cystine or reduced Hpoic acid to oxidized Hpoic acid. Many enzymes depend on free SH groups for activation—deactivation reactions. The oxidation—reduction of glutathione (Glu-Cys-Gly) depends on the sulfhydryl group from cysteine. 

It appears that chromium(III) is an essential trace element in mammalian metabolism and, together with insulin, is responsible for the clearance of glucose from the blood-stream. Tungsten too has been found to have a role in some enzymes converting CO2 into formic acid but, from the point of view of biological activity, the focus of interest in this group is unquestionably on molybdenum. 

Meglitinide contains a benzamide group. Meglitinide-related compounds such as nateglinide are non-sulfonylurea oral hypoglycemic drugs used in the treatment of type 2 (non-insulin dependent) diabetes mellitus. 

Neutral endopeptidase (NEP, nephrilysin) is an enzyme that preferentially catalyzes cleavage at the amino group of hydrophobic residues of the B-chain of insulin... 

Figure 2. Mechanism of PDH. The three different subunits of the PDH complex in the mitochondrial matrix (E, pyruvate decarboxylase E2, dihydrolipoamide acyltrans-ferase Ej, dihydrolipoamide dehydrogenase) catalyze the oxidative decarboxylation of pyruvate to acetyl-CoA and CO2. E, decarboxylates pyruvate and transfers the acetyl-group to lipoamide. Lipoamide is linked to the group of a lysine residue to E2 to form a flexible chain which rotates between the active sites of E, E2, and E3. E2 then transfers the acetyl-group from lipoamide to CoASH leaving the lipoamide in the reduced form. This in turn is oxidized by E3, which is an NAD-dependent (low potential) flavoprotein, completing the catalytic cycle. PDH activity is controlled in two ways by product inhibition by NADH and acetyl-CoA formed from pyruvate (or by P-oxidation), and by inactivation by phosphorylation of Ej by a specific ATP-de-pendent protein kinase associated with the complex, or activation by dephosphorylation by a specific phosphoprotein phosphatase. The phosphatase is activated by increases in the concentration of Ca in the matrix. The combination of insulin with its cell surface receptor activates PDH by activating the phosphatase by an unknown mechanism.

The temporal correlation between in vitro and in vivo release of insulin was quite good. To induce diabetes, two groups of rats were administered 65 mg/kg of streptozotocin in 0.1 M citrate buffer, pH 4.5. Within several days, the animals had become diabetic, as evidenced by blood glucose levels of approximately 400 mg/dl, and substantial output of glucose in their urine. One group of these animals was then injected subcutaneously with 40-50 mg of 15% insulin-loaded PCPP-SA 50 50 microspheres, 850-1000 pm in diameter. A third group of animals receiving no treatment served as a control. 

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