Pathophysiology and treatment of type 2 diabetes: perspectives on the past, present, and future

In the paper

“Together these genes do not appear to explain much of the genetic basis of the disease with the use of genotype risk scores only slightly improving prediction of subsequent diabetes compared to common clinical risk factors22,23.”

What the sources say

• Supported

  The Discussion says the 18 SNPs account for a minority of diabetes heritability. It also concludes that the genotype score did not substantially improve prediction beyond common phenotypic risk factors. (LLM, conf=0.93)

  cites [22] Meigs, 2008, Genotype score in addition to common risk factors for prediction of type 2 diabetes, N Engl J Med source
• Partly supported

  The Abstract and Discussion report that adding known DNA variants to clinical risk factors only slightly improved prediction of future type 2 diabetes (AUC 0.74 to 0.75). The paper also reports low discriminatory power for the genes alone, but it does not establish how much of the disease’s genetic basis these genes explain. (LLM, conf=0.83)

  cites [23] Lyssenko, 2008, Clinical risk factors, DNA variants, and the development of type 2 diabetes, N Engl J Med sourceExperimental — accuracy not yet measured

In the paper

“Further analyses from TODAY show that in youth with type 2 diabetes dyslipidaemia162 and hypertension163 are common and worsen over time.”

What the sources say

• ?Could not verify

  The Conclusions discuss exenatide, insulin glargine and β-cell function over three years, not TODAY findings in youth. Searches for TODAY, youth, dyslipidaemia and hypertension found no passage addressing whether those conditions are common or worsen over time. (LLM, conf=0.76)

  cites [162] Bunck, 2011, Effects of exenatide on measures of β-cell function after 3 years in metformin-treated patients with type 2 diabetes, Diabetes Care sourceExperimental — accuracy not yet measured
• Not checked yetcites [163] Pan, 1997, Effects of diet and exercise in preventing NIDDM in people with impaired glucose tolerance. The Da Qing IGT and Diabetes Study, Diabetes Care source

In the paper

“individuals with “early maturity onset diabetes” produced insulin and secreted this hormone in response to nutrient ingestion2.”

What the sources say

• Not checked yetcites [2] Yalow, 1960, Immunoassay of endogenous plasma insulin in man, J Clin Invest source

In the paper

“this contributed to increased glucose production by the liver and decreased glucose uptake in muscle and adipose tissue5.”

What the sources say

• Not checked yetcites [5] Reaven, 1988, Banting lecture 1988. Role of insulin resistance in human disease, Diabetes source

In the paper

“the reality is that these disturbances are a continuum in which the magnitude of the reduction in β-cell function determines the degree of elevation in plasma glucose.”

In the paper

“The basis for this loss is multifactorial, and includes glucolipotoxicity32 and amyloid deposition that result in β-cell apoptosis through oxidative as well as endoplasmic reticulum stress31.”

What the sources say

• Not checked yetcites [31] Jurgens, 2011, β-cell loss and β-cell apoptosis in human type 2 diabetes are related to islet amyloid deposition, Am J Pathol source
• Not checked yetcites [32] Poitout, 2008, Glucolipotoxicity: fuel excess and β-cell dysfunction, Endocr Rev source

In the paper

“While a few loci are associated with obesity and insulin resistance, the vast majority are linked to the β-cell21.”

What the sources say

• Not checked yetcites [21] McCarthy, 2010, Genomics, type 2 diabetes, and obesity, N Engl J Med source

In the paper

“it is clear that the disease process is heterogeneous, including other pathogenic factors discussed subsequently.”

In the paper

“Obesity is frequently characterized by systemic inflammation and preclinical evidence links systemic inflammation to β-cell dysfunction63,64.”

What the sources say

• Not checked yetcites [63] Dula, 2010, Evidence that low-grade systemic inflammation can induce islet dysfunction as measured by impaired calcium handling, Cell Calcium source
• Not checked yetcites [64] Nicol, 2013, Pancreatic inflammation and increased islet macrophages in insulin-resistant juvenile primates, J Endocrinol source

In the paper

“They are endogenous ligands of the farnesoid X receptor (FXR), their activation of FXR resulting in the release of fibroblast growth factor (FGF) 1943.”

What the sources say

• Not checked yetcites [43] Potthoff, 2012, Endocrine fibroblast growth factors 15/19 and 21: from feast to famine, Genes Dev source

In the paper

“GLP-1 is the more important of these hormones acting on both β- and α-cells to enhance insulin and suppress glucagon secretion, respectively37.”

What the sources say

• Not checked yetcites [37] Drucker, 2006, The biology of incretin hormones, Cell Metab source

In the paper

“Direct effects of inflammation on β-cells arise from activation of the intra-islet immune response, the strongest support being for a role for interleukin-1β (IL-1β)71.”

What the sources say

• Not checked yetcites [71] Donath, 2003, Inflammatory mediators and islet β-cell failure: a link between type 1 and type 2 diabetes, J Mol Med (Berl) source

In the paper

“Analyses from ACCORD suggest that the individual likely to be at greatest risk of an adverse outcome to aggressive glucose lowering had a longer duration of diabetes, poor glucose control at the time of commencing intensive insulin therapy, and did not demonstrate an immediate glucose lowering response125.”

What the sources say

• Not checked yetcites [125] Gelling, 2003, Lower blood glucose, hyperglucagonemia, and pancreatic α cell hyperplasia in glucagon receptor knockout mice, Proc Natl Acad Sci USA source

In the paper

“Despite differential weight loss for over 10 years and improvements in many cardiovascular risk factors, including blood pressure and lipids, lifestyle change did not reduce cardiovascular events compared to diabetes support and education (control)133.”

What the sources say

• Not checked yetcites [133] Adams, 2013, LY2405319, an engineered FGF21 variant, improves the metabolic status of diabetic monkeys, PLoS One source

In the paper

“consistent with the multifactorial approach in the Steno 2 Study that demonstrated a reduction in both cardiovascular and microvascular events which was sustained even after cessation of the initial glucose, blood pressure and lipid lowering regimens132.”

What the sources say

• Not checked yetcites [132] Kliewer, 2010, Fibroblast growth factor 21: from pharmacology to physiology, Am J Clin Nutr source

In the paper

“Such a microvascular benefit was also shown in ADVANCE, the magnitude being related to the degree of glucose control and affecting largely renal outcomes (essentially a reduction in microalbuminuria)124.”

What the sources say

• Not checked yetcites [124] Talchai, 2012, Pancreatic β cell dedifferentiation as a mechanism of diabetic β cell failure, Cell source

In the paper

“Thus, based on five separate studies, it would seem that current approaches involving intensification of glucose control are valuable for reducing microvascular complications but are not effective in reducing cardiovascular events, possibly even being harmful in those with advanced type 2 diabetes.”

In the paper

“This may have been because large proportions of subjects in both groups received medical treatment for these risk factors.”

In the paper

“serum from type 2 diabetic patients treated with glargine activates insulin receptors A and B similarly to NPH insulin and does not increase signalling through the IGF-1 receptor128.”

What the sources say

• Not checked yetcites [128] Agius, 2007, New hepatic targets for glycaemic control in diabetes, Best Pract Res Clin Endocrinol Metab source

In the paper

“Whereas the onset of glucose lowering with the other two medications was slower, it was most sustained with rosiglitazone, with metformin demonstrating an intermediate pattern.”

What the sources say

• Not checked yetcites [138] Lindsay, 2003, Subcutaneous adipose 11 beta-hydroxysteroid dehydrogenase type 1 activity and messenger ribonucleic acid levels are associated with adiposity and insulinemia in Pima Indians and Caucasians, J Clin Endocrinol Metab source

In the paper

“Glibenclamide produced the greatest initial reduction in glycaemia, but was poorest in maintaining glucose control.”

What the sources say

• Not checked yetcites [138] Lindsay, 2003, Subcutaneous adipose 11 beta-hydroxysteroid dehydrogenase type 1 activity and messenger ribonucleic acid levels are associated with adiposity and insulinemia in Pima Indians and Caucasians, J Clin Endocrinol Metab source

In the paper

“These trials have more or less uniformly demonstrated a benefit, with lifestyle more efficacious than all medications with the exception of the thiazolidinediones140–152.”

What the sources say

• Not checked yetcites [140] Gathercole, 2013, 11β-hydroxysteroid dehydrogenase 1: translational and therapeutic aspects, Endocr Rev source
• Not checked yetcites [141] Tschöp, 2012, Outstanding Scientific Achievement Award Lecture 2011: defeating diabesity: the case for personalized combinatorial therapies, Diabetes source
• Not checked yetcites [142] Tan, 2013, Coadministration of glucagon-like peptide-1 during glucagon infusion in humans results in increased energy expenditure and amelioration of hyperglycemia, Diabetes source
• Not checked yetcites [143] 1998, Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33), Lancet source
• Not checked yetcites [144] Gerstein, 2008, Effects of intensive glucose lowering in type 2 diabetes, N Engl J Med source
• Not checked yetcites [145] Duckworth, 2009, Glucose control and vascular complications in veterans with type 2 diabetes, N Engl J Med source
• Not checked yetcites [146] Gerstein, 2012, Basal insulin and cardiovascular and other outcomes in dysglycemia, N Engl J Med source
• Not checked yetcites [147] Patel, 2008, Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes, N Engl J Med source
• Not checked yetcites [148] Riddle, 2010, Epidemiologic relationships between A1C and all-cause mortality during a median 3·4-year follow-up of glycemic treatment in the ACCORD trial, Diabetes Care source
• Not checked yetcites [149] Ismail-Beigi, 2010, Effect of intensive treatment of hyperglycaemia on microvascular outcomes in type 2 diabetes: an analysis of the ACCORD randomised trial, Lancet source

In the paper

“Thus, intensive lifestyle change in patients with type 2 diabetes has benefits, but unfortunately not on cardiovascular outcomes which remain the major determinant of premature mortality in type 2 diabetes.”

In the paper

“Both microalbuminuria and retinopathy increase with diabetes duration and severity is related to glycaemic control163,164.”

What the sources say

• Not checked yetcites [163] Pan, 1997, Effects of diet and exercise in preventing NIDDM in people with impaired glucose tolerance. The Da Qing IGT and Diabetes Study, Diabetes Care source
• Not checked yetcites [164] Tuomilehto, 2001, Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance, N Engl J Med source

In the paper

“The results of SAVOR-TIMI 53 (NCT01107886) and EXAMINE (NCT00968708) were recently released and showed no increased risk of cardiovascular events with the DPP-4 inhibitors saxagliptin96 and alogliptin97, respectively.”

What the sources say

• Not checked yetcites [96] Scirica, 2013, Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus, N Engl J Med source
• Not checked yetcites [97] White, 2013, Alogliptin after acute coronary syndrome in patients with type 2 diabetes, N Engl J Med source

In the paper

“The disease’s course in youth appears to be more aggressive than in adults, with the differential impact of the interventions being the result of a greater improvement in β-cell function160.”

What the sources say

• Not checked yetcites [160] Rejeski, 2012, Lifestyle change and mobility in obese adults with type 2 diabetes, N Engl J Med source

In the paper

“While the number of pancreas-related events in SAVOR-TIMI 53 and EXAMINE were too small to be definitive, there was no evidence for a marked excess of such events with either medication.”

What the sources say

• Not checked yetcites [96] Scirica, 2013, Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus, N Engl J Med source
• Not checked yetcites [97] White, 2013, Alogliptin after acute coronary syndrome in patients with type 2 diabetes, N Engl J Med source

In the paper

“However, despite good rationale for approval of interventions to delay the onset of diabetes159, no medication has yet received official sanction as a preventative treatment.”

What the sources say

• Not checked yetcites [159] Foster, 2009, A randomized study on the effect of weight loss on obstructive sleep apnea among obese patients with type 2 diabetes: the Sleep AHEAD study, Arch Intern Med source

In the paper

“The pathogenesis of the syndrome in children is also critically determined by β-cell function loss with the degree of residual β-cell function determining glucose control in recently diagnosed patients160.”

What the sources say

• Not checked yetcites [160] Rejeski, 2012, Lifestyle change and mobility in obese adults with type 2 diabetes, N Engl J Med source

In the paper

“The TODAY (Treatment Options for Type 2 Diabetes in Adolescents and Youth) study examined the impact of lifestyle and medications in a young cohort with diabetes duration of less than a year and found glycaemia to be best managed by the combination of rosiglitazone and metformin, with the addition of lifestyle to metformin being no better than metformin alone161.”

What the sources say

• Not checked yetcites [161] Kahn, 2006, Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy, N Engl J Med source

In the paper

“Given that current treatment approaches do not prevent or slow the loss of β-cell function, there is clearly an urgent need for alternative approaches.”

In the paper

“While current treatment algorithms are less prescriptive than before and advocate a more personalized approach to the choice of medications and treatment targets for type 2 diabetes131”

What the sources say

• Not checked yetcites [131] Ma, 2011, PTP1B inhibitor improves both insulin resistance and lipid abnormalities in vivo and in vitro, Mol Cell Biochem source

In the paper

“However, these hypotheses are based on results from the Swedish Obese Subjects Study in which subjects were not randomized and the control group was contemporaneously matched, only received conventional treatment, and differed by a number of characteristics at baseline.”

What the sources say

• Not checked yetcites [173] Gerstein, 2006, Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomised controlled trial, Lancet source
• Not checked yetcites [174] DeFronzo, 2011, Pioglitazone for diabetes prevention in impaired glucose tolerance, N Engl J Med source
• Not checked yetcites [175] Zinman, 2010, Low-dose combination therapy with rosiglitazone and metformin to prevent type 2 diabetes mellitus (CANOE trial): a double-blind randomised controlled study, Lancet source