Roux-en-Y gastric bypass (RYGB) surgery reverses diabetes (T2DM) in ~80% of patients. Ghrelin regulates glucose homeostasis, but its role in T2DM remission after RYGB surgery is unclear. Nine obese T2DM subjects underwent a mixed meal tolerance test before and at 1 and 12 months after RYGB. Changes in ghrelin, body weight, GLP-1, glucose tolerance, and insulin sensitivity were measured. At 1 month, body weight, glycemia and insulin sensitivity were improved, while ghrelin concentrations were reduced (p<0.05). After 12 months, body weight and fasting glucose were reduced (30% and 16% respectively; p<0.05) and insulin sensitivity was enhanced (3-fold; p<0.05). Ghrelin suppression improved by 32% at 12 months (p<0.05), and this was associated with weight loss (R = 0.72, p=0.03), enhanced insulin sensitivity (R = -0.78, p=0.01) and peak post-prandial GLP-1 (R = -0.73, p=0.03). These data suggest that post-prandial ghrelin suppression may be part of the mechanism that contributes to diabetes remission after RYGB surgery.

In spite of major developments in insulin production, purification, pharmaceutical formulation and methods of delivery, problems remain both in the day to day management of insulin-treated diabetes and with regard to its long-term complications. The risks of hypoglycaemia and weight gain are major concerns particularly for the patient, and the persistence of microvascular and premature macrovascular complications as the main causes of morbidity and mortality in both type 1 and type 2 diabetes is a constant reminder that our therapeutic and management strategies are inadequate. One clear and striking difference between currently available insulin treatments and normal physiology is the relative difference in exposure to insulin of the liver versus peripheral tissues. Hepatoselective insulin analogues have the potential to restore the normal hepatic to peripheral gradient in insulin action. Here, we discuss the possible therapeutic potential that such analogues may have over currently available insulin preparations. These benefits could include a lower risk of hypoglycaemia, less weight gain and a potential reduction in microvascular and macrovascular complications. We explore the evolution of insulin with hepatoselectivity in mind and possible strategies to create hepatoselective insulins.

AIMS:

To characterize the incidence of type 2 diabetes in the UK over the previous 20 years; and determine if there has been an increase in people aged 40 years or less at diagnosis.

METHODS:

For this retrospective cohort study, patients newly diagnosed with type 2 diabetes between 1991 and 2010 were identified from the UK Clinical Practice Research Datalink (CPRD). Patient data were grouped into 5-year intervals by year of diagnosis and age at diagnosis. A standardized incidence ratio (SIR) was determined (1991-1995 = 100). The percentage of newly diagnosed patients for each age group and aged ≤40 years was calculated for each 5-year calendar period. The incidence rate by age and 5-year calendar period was also determined.

RESULTS:

In 2010, the crude incidence rate of type 2 diabetes was 515 per 100,000 population. The overall SIR increased to 158 (95% CI 157-160, p < 0.001), 237 (235-238, p < 0.001) and 275 (273-276, p < 0.001) for 1996-2000, 2001-2005 and 2006-2010, respectively. For those ≤40, the respective values were 217 (209-226, p < 0.001), 327 (320-335, p < 0.001) and 598 (589-608, p < 0.001). An increase in incidence occurred with increasing 5-year calendar period. The incidence of type 2 diabetes was higher for males after the age of 40 and higher for females aged ≤40. The percentage of patients aged ≤40 years at diagnosis increased with each increasing 5-year calendar period (5.9, 8.4, 8.5 and 12.4%, respectively).

CONCLUSIONS:

There was a significant increase in the incidence of diagnosed type 2 diabetes between 1991 and 2010 and the proportion of people diagnosed at a relatively early age has increased markedly.

AIMS:

There is limited evidence regarding the association between physical activity and vascular complications, particularly microvascular disease, in patients with type 2 diabetes.

MATERIALS AND METHODS:

From the 11,140 patients in the ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron modified release Controlled Evaluation) trial the effect of physical activity, categorized as none, mild, moderate or vigorous, and the number of sessions within a week, was examined in multivariable regression models adjusted for potential confounders. The study end-points were major cardiovascular events, microvascular complications and all-cause mortality.

RESULTS:

Forty-six percent of participants reported undertaking moderate to vigorous physical activity for >15 minutes at least once in the previous week. During a median of 5 years of follow up, 1,031 patients died, 1,147 experienced a major cardiovascular event and 1,136 a microvascular event. Compared to patients who undertook no or mild physical activity, those reporting moderate to vigorous activity had a decreased risk of cardiovascular events (HR 0.78, 95% CI 0.69-0.88, p < 0.0001), microvascular events (HR 0.85, 95% CI 0.76-0.96, p0.010) and all-cause mortality (HR 0.83, 95% CI 0.73-0.94, p0.0044).

CONCLUSIONS:

Moderate to vigorous, but not mild, physical activity is associated with a reduced incidence of cardiovascular events, microvascular complications and all-cause mortality in patients with type 2 diabetes.

Treat-to-target trial designs compare investigational insulins with a standard insulin. Treat-to-target trials force-titrate insulin dosages to achieve a prespecified treatment goal. With comparable glycemic control, comparisons of safety endpoints such as hypoglycemia can be made to establish the risk-benefit profile of the new insulin. Glargine vs NPH showed comparable A1C reductions; however, A1C <7% without associated nocturnal hypoglycemia was reached in more patients on glargine and overall hypoglycemia was lower. Detemir vs glargine demonstrated noninferiority between the groups; however, with less weight gain and more injection site reactions with detemir. Detemir/aspart vs glargine/aspart demonstrated noninferiority between the treatments, however, with less weight gain in the detemir group but comparable risk of hypoglycemia. Degludec in combination with aspart vs glargine/aspart showed comparable A1C reductions. However, degludec-treated patients had less overall hypoglycemia and less nocturnal hypoglycemia. Because insulin titrations are guided by goal attainment with each treatment, treat-to-target trials enable clinicians to determine differences in non-glycemic treatment effects, such as rates of hypoglycemia and weight gain, at the same level of glycemic control.

The main pathogenesis of type 2 diabetes mellitus (T2DM) includes insulin resistance and pancreatic islet dysfunction. Metformin, which attenuates insulin resistance, has been recommended as the first-line antidiabetic medication. Dipeptidyl peptidase-4 (DPP-4) inhibitors are novel oral hypoglycemic agents that protect glucagon-like peptide-1 (GLP-1) from degradation, maintain the bioactivity of endogenous GLP-1, and thus improve islet dysfunction. Results from clinical trials have demonstrated that the combination therapy of DPP-4 inhibitors and metformin (as an add-on, an initial combination, or a fixed-dose combination) provides excellent efficacy and safety in patients with T2DM. Moreover, recent studies have suggested that metformin enhances the biological effect of GLP-1 via increasing GLP-1 secretion, suppressing activity of DPP-4, and upregulating the expression of GLP-1 receptor in pancreatic β cells. Conversely, DPP-4 inhibitors have a favorable effect on insulin sensitivity in patients with T2DM. Therefore, the combination of DPP-4 inhibitors and metformin provides an additive or even synergistic effect on metabolic control in patients with T2DM. This article provides an overview of clinical evidence and discusses the rationale for the combination therapy of DPP-4 inhibitors and metformin.

AIMS:

Sodium-glucose cotransporter 2 (SGLT2) reabsorbs glucose and sodium in the renal proximal tubule. Dapagliflozin, an SGLT2 inhibitor, targets hyperglycemia in type 2 diabetes by increasing renal glucose excretion. To investigate whether the parallel occurring sodium loss would have diuretic-like physiologic effects, we compared dapagliflozin and hydrochlorothiazide (HCTZ) effects on 24-hour blood pressure (BP), body weight, plasma volume, and glomerular filtration rate (GFR).

METHODS:

In this randomized, placebo-controlled, double-blind trial, 75 subjects with type 2 diabetes were assigned placebo, dapagliflozin 10 mg/day, or HCTZ 25 mg/day. Changes from baseline blood pressure, body weight, plasma volume and GFR were assessed after 12 weeks of treatment.

RESULTS:

Subjects' mean age was 56 years, T2DM duration 6.3 years, and HbA1c 7.5%. Treatment with placebo, dapagliflozin, or HCTZ resulted in changes from baseline in 24-hour ambulatory mean systolic blood pressure (SBP) of -0.9 (95%CI -4.2, +2.4), -3.3 (95%CI -6.8, +0.2), and -6.6 (95%CI -9.9, -3.2) mmHg, respectively at week 12, adjusted for baseline SBP. Body weight decreased with dapagliflozin and HCTZ. In a sub-study plasma volume appeared to decrease with dapagliflozin but did not change with placebo or HCTZ treatment. Dapagliflozin induced a greater reduction in GFR (-10.8%; 95%CI -14.6, -6.7) relative to placebo (-2.9%; 95% CI -6.9, +1.2) or HCTZ (-3.4%; 95%CI -7.3, +0.6).

CONCLUSIONS:

Dapagliflozin-induced SGLT2 inhibition for 12 weeks is associated with reductions in 24-hour BP, body weight, GFR, and possibly plasma volume. Cumulatively, these effects suggest that dapagliflozin may have a diuretic-like capacity to lower BP in addition to beneficial effects on glycemic control. www.clinicaltrials.gov NCT00976495.

AIMS:

Adenosine triphosphate sensitive potassium (KATP ) channel activity is cardioprotective during ischemia. One of the purported mechanisms for sulfonylurea adverse effects is through inhibition of these channels. The purpose of this study is to examine whether patients using KATP channel inhibitors at the time of an acute coronary syndrome are at greater risk of death or heart failure (HF) than those not exposed.

MATERIALS AND METHODS:

Using linked administrative databases we identified all adults who had an acute coronary syndrome between April 2002 and October 2006 (n= 21 023).

RESULTS:

Within 30 days of acute coronary syndrome, 5.3% of our cohort died and 15.6% were diagnosed with HF. Individuals with diabetes exhibited significantly higher risk of death (adjusted OR 1.20, 95% CI 1.03 to 1.40) and death or HF (aOR 1.73, 95% CI 1.59 to 1.89) than individuals without diabetes. However, there was no significantly increased risk of death (aOR 1.00, 95% CI 0.76-1.33) or death/HF (aOR 1.06, 95% CI 0.89 - 1.26) in patients exposed to KATP channel inhibitors versus patients not exposed to KATP channel inhibitors prior to their acute coronary syndrome.

CONCLUSIONS:

Diabetes is associated with an increased risk of death or HF within 30 days of an acute coronary syndrome. However, we did not find any excess risk of death or HF associated with use of KATP channel inhibitors at the time of an acute coronary syndrome, raising doubts about the hypothesis that sulfonylureas inhibit the cardioprotective effects of myocardial KATP channels.

There is a growing body of evidence to support a connection between diabetes (predominantly type 2), obesity and cancer. Multiple meta-analyses of epidemiological data show that people with diabetes are at increased risk of developing many different types of cancers, along with an increased risk of cancer mortality. Several pathophysiological mechanisms for this relationship have been postulated, including insulin resistance and hyperinsulinaemia, enhanced inflammatory processes, dysregulation of sex hormone production and hyperglycemia. In addition to these potential mechanisms, a number of common risk factors, including obesity, may be behind the association between diabetes and cancer. Indeed, obesity is associated with an increased risk of cancer and diabetes. Abdominal adiposity has been shown to play a role in creating a systemic pro-inflammatory environment, which could result in the development of both diabetes and cancer. Here, we examine the relationship between diabetes, obesity and cancer, and investigate the potential underlying causes of increased cancer risk in individuals with diabetes. Current treatment recommendations for reducing the overall disease burden are also explored and possible areas for future research are considered.