 fingers and hope for the best.
The rest of the players listed on the injury report should play (except for rookie RB Alex Green, but he only played on special teams against the Saints). The entire injury report is after the jump.Diabetes mellitus is an entity of considerable morbidity comprising a spectrum of multisystem dysfunctions stemming from the combination of insulin resistance and inadequate insulin secretion. Management of diabetes, akin to a tightrope walk, requires a comprehensive understanding of various factors such as over-all clinical picture, adverse effect profile, the complex of inter-play of drugs, etc. More than two-thirds of people with type 2 diabetes will eventually require more than one oral agent, with or without insulin. There is a perpetually increasing newer range of antidiabetic drugs targeting novel aspects of diabetes which warrant adequate awareness by the treating clinicians. The newer antidiabetic drugs of different classes are discussed below.
Sodium-dependent glucose co-transporters (SGLT) are found in the intestinal mucosa of the small intestine and the proximal tubules of the nephrons. Two types of SGLT are of considerable importance in diabetes-SGLT1 and SGLT2 (members of genes SLC5A1 and A2, respectively). [1] Intestines predominantly sport SGLT1 whereas the proximal tubules of the nephrons display both SGLT2 and SGLT1. A sodium-to-glucose co-transport ratio of SGLT1 is 2:1 and that of SGLT2 is 1:1 and while the former contributes 2% to glucose reabsorption, the latter contributes 98%. [2] Hence SGLT2 inhibition enables us to considerably reduce transcellular epithelial glucose reabsorption. SGLT2 inhibition is independent of glucose-dependent insulin secretion by the pancreatic β cells.
Dapagliflozin, the notable molecule in the class of SGLT2 inhibitors, reduces blood glucose levels in an insulin-independent manner by inhibition of SGLT2-mediated reabsorption of glucose in the kidney. Dapagliflozin sported a comparable 52-week glycemic efficacy with glipizide and in addition, unlike the latter, resulted in reduced weight and less hypoglycemia. [3] However, the FDA (Food and Drug Administration) presented an unfavorable review of the drug owing to increased incidence of breast and bladder cancers and hepatotoxicity. [4] Remogliflozin, another SGLT2 inhibitor, is found to be potent and highly selective. In experimental models, its prodrug remogliflozin etabonate increased urinary glucose excretion in a dose-dependent manner which in turn inhibited the increase in plasma glucose after glucose loading without stimulating insulin secretion. [5] Sergliflozin etabonate, in a study, showed superiority over gliclazide and showed reductions in glycated hemoglobin and improved glycemic control without resulting in insulin secretion, hypoglycemia, and body weight gain. [6] Canagliflozin and other similar molecules are being evaluated with encouraging results.
The adverse effects of SGLT2 inhibitors may include fatigue, hypoglycemia, increased urine output, increased hematocrit, and mycotic genital or urinary tract infections.
Adverse effects, including nasopharyngitis and upper respiratory infections (probably via immunomodulation), [16] headache, nausea, skin reactions and rarely hypersensitivity reactions, and pancreatitis (probably via ductal proliferation and metaplasia) [17] are reported with DPP IV inhibitors.
Exenatide, a GLP-1 analogue and insulin secretagogue with glucoregulatory effects. It is recommended for use as adjunctive therapy to improve glycemic control in patients who are taking metformin, or a combination of metformin and a sulfonylurea, but have not achieved adequate glycemic control. Exenatide augments glucose-dependent insulin secretion by the pancreatic β:-cell. In a study, exenatide once weekly brought sustained improvements in glycemic control (HbA1C and FPG) and body weight through 52 weeks of treatment. [19] Weight-related quality of life, health utility, psychological well-being, and diabetes treatment satisfaction are all shown to be better when exenatide is used in combination with metformin. [20] The side effect profile of exenatide includes hypoglycemia (more upon combination therapy with sulfonylureas and thiazolidinediones), nausea, vomiting, diarrhea, heartburn, indigestion, dizziness, headache, and pancreatitis. Development of anti-exenatide antibodies may also be seen.
Glucokinase (also called hexokinase IV or D) owing to its glucose sensor role in pancreatic β-cells and being the rate-controlling enzyme for hepatic glucose clearance and glycogen synthesis is known to have an exceptionally high impact on glucose homeostasis. Glucokinase activators (GKAs) stimulate insulin biosynthesis and secretion and augment glucose metabolism and related processes in other glucokinase-expressing cells via GKA-mediated increase in the affinity of glucokinase for glucose and its maximal catalytic rate.­ [27] GKAs mediate their antidiabetic effects via generalized enhancement of β-cell function and through fasting restricted changes in glucose turnover. Piragliatin, a GKA, has shown an acute glucose-lowering action in patients with mild type 2 diabetes. [28] An experimental GKA molecule ZYGK1 showed promising efficacy in controlling both fasting and non-fasting blood glucose. [29] The side effects although rare of GKAs are hypoglycemia, fatty liver, and hyperlipidemia.
To induce immune tolerance via monoclonal antibodies has been tried as a way to prevent and effectively treat diabetes. Otelixizumab, an anti-CD3 monoclonal antibody, is known to stimulate C-peptide levels and reduce insulin requirement in type 1 diabetes. [35] Similarly studies with teplizumab are also reassuring. [36] Other monoclonal antibodies such as anti-CD20, [37] anti-CTGF, [38] anti-IL-1β,[39] have shown promising results and are yet to be approved.
Timed bromocriptine (centrally-acting dopamine D2 receptor agonist) is believed to act on circadian neuronal activities within the hypothalamus to reset abnormally elevated hypothalamic drive for increased plasma glucose, triglyceride, and free fatty acid levels in fasting and postprandial states in insulin-resistant patients. Its use as monotherapy and in combination with other OHAs is shown to reduce HbA1c, plasma triglyceride, and FFA concentrations in type 2 diabetic patients. [40] Side effects include nausea, fatigue, vomiting, headache, dizziness, orthostatic hypotension, and syncope, the latter two upon initiation or dose escalation.
Chromium (Cr) may reduce myocellular lipids and enhance insulin sensitivity in subjects with type 2 diabetes mellitus independent of its effects on weight or hepatic glucose production. [41] Clinical response to Cr is more likely in insulin-resistant type 2 diabetics with elevated fasting glucose and A1C levels. It also has anti-inflammatory activity apparently mediated by elevated blood vitamin C and adiponectin and inhibition of NFκB, Akt, and Glut-2 and increased IRS-1 gene activation.[42] Sodium tungstate is known to preserve the pancreatic β-cell function in diabetics and normalize the activity of sucrase and SGLT1 in the brush-border membrane of enterocytes. [43] A combination of hyperglycemia-independent pathways are postulated to explain its antidiabetic effects. [44] Vanadium is known to mimic most effects of insulin on the main target tissues of the hormone in vitro and it is shown to induce a sustained fall in blood glucose levels in insulin-deficient diabetic rats, and improve glucose homeostasis in obese, insulin-resistant diabetic rodents (in vivo). It has shown antidiabetic effects in phase II trials [45] although another study showed no such benefits. [46] Proxyfan, a central histamine H3 receptor ligand, is shown to significantly improve glucose excursion by increasing plasma insulin levels via a glucose-independent mechanism. [47] Aspartame, guargum, and glucomannan have all displayed notable benefits in glycemic control either singly or as combinations.
There is rapid and accelerated progress in the antidiabetics drug-development front that runs parallel to our ever evolving comprehension of the pathophysiology of diabetes. Clinicians need to be abreast of this plethora of newer antidiabetic drugs coming up, their efficacy, adverse effect profile and stand in diabetes management that empowers them to better manage diabetes.
I thank my colleagues and staff of Internal Medicine.
1. Wright EM, Hirayama BA, Loo DF. Active sugar transport in health and disease. J Intern Med 2007;261:32-43.
2. Sabino-Silva R, Mori RC, David-Silva A, Okamoto MM, Freitas HS, Machado UF. The Na(+)/glucose cotransporters: From genes to therapy. Braz J Med Biol Res 2010;43:1019-26.
3. Nauck MA, Del Prato S, Meier JJ, Durán-García S, Rohwedder K, Elze M, et al. Dapagliflozin versus glipizide as add-on therapy in patients with type 2 diabetes who have inadequate glycemic control with metformin: A randomized, 52-week, double-blind, active-controlled noninferiority trial. Diabetes Care 2011;34:2015-22.
4. FDA Briefing Document. NDA 202293. Dapagliflozin Tablets, 5 and 10 mg. Sponsor: Bristol-Myers Squibb. Advisory Committee Meeting, July 19, 2011. Available from: http://www.fda