AimsCanagliflozin is a sodium glucose co-transporter 2 inhibitor in development for treatment of type 2 diabetes mellitus (T2DM). This study evaluated the efficacy and safety of canagliflozin in subjects with T2DM and stage 3 chronic kidney disease [CKD; estimated glomerular filtration rate (eGFR) ≥30 and <50 ml/min/1.73 m2].MethodsIn this randomized, double-blind, placebo-controlled, phase 3 trial, subjects (N = 269) received canagliflozin 100 or 300 mg or placebo daily. The primary efficacy endpoint was change from baseline in HbA1c at week 26. Prespecified secondary endpoints were change in fasting plasma glucose (FPG) and proportion of subjects reaching HbA1c <7.0%. Safety was assessed based on adverse event (AE) reports; renal safety parameters (e.g. eGFR, blood urea nitrogen and albumin/creatinine ratio) were also evaluated.ResultsBoth canagliflozin 100 and 300 mg reduced HbA1c from baseline compared with placebo at week 26 (–0.33, –0.44 and –0.03%; p < 0.05). Numerical reductions in FPG and higher proportions of subjects reaching HbA1c < 7.0% were observed with canagliflozin 100 and 300 mg versus placebo (27.3, 32.6 and 17.2%). Overall AE rates were similar for canagliflozin 100 and 300 mg and placebo (78.9, 74.2 and 74.4%). Slightly higher rates of urinary tract infections and AEs related to osmotic diuresis and reduced intravascular volume were observed with canagliflozin 300 mg compared with other groups. Transient changes in renal function parameters that trended towards baseline over 26 weeks were observed with canagliflozin.ConclusionCanagliflozin improved glycaemic control and was generally well tolerated in subjects with T2DM and Stage 3 CKD.

OBJECTIVETo evaluate long-term clinical outcomes and survival in young-onset type 2 diabetes (T2DM) compared with type 1 diabetes (T1DM) with a similar age of onset.RESEARCH DESIGN AND METHODSRecords from the Royal Prince Alfred Hospital Diabetes Clinical Database, established in 1986, were matched with the Australian National Death Index to establish mortality outcomes for all subjects until June 2011. Clinical and mortality outcomes in 354 patients with T2DM, age of onset between 15 and 30 years (T2DM15–30), were compared with T1DM in several ways but primarily with 470 patients with T1DM with a similar age of onset (T1DM15–30) to minimize the confounding effect of age on outcome.RESULTSFor a median observation period of 21.4 (interquartile range 14–30.7) and 23.4 (15.7–32.4) years for the T2DM and T1DM cohorts, respectively, 71 of 824 patients (8.6%) died. A significant mortality excess was noted in T2DM15–30 (11 vs. 6.8%, P = 0.03), with an increased hazard for death (hazard ratio 2.0 [95% CI 1.2–3.2], P = 0.003). Death for T2DM15–30 occurred after a significantly shorter disease duration (26.9 [18.1–36.0] vs. 36.5 [24.4–45.4] years, P = 0.01) and at a relatively young age. There were more cardiovascular deaths in T2DM15–30 (50 vs. 30%, P < 0.05). Despite equivalent glycemic control and shorter disease duration, the prevalence of albuminuria and less favorable cardiovascular risk factors were greater in the T2DM15–30 cohort, even soon after diabetes onset. Neuropathy scores and macrovascular complications were also increased in T2DM15–30 (P < 0.0001).CONCLUSIONSYoung-onset T2DM is the more lethal phenotype of diabetes and is associated with a greater mortality, more diabetes complications, and unfavorable cardiovascular disease risk factors when compared with T1DM.

Canagliflozin improved glycaemic control and was generally well tolerated in patients with T2DM and within a subset of Stage 3 CKD over 52 weeks.

OBJECTIVE -We studied the relationships of diabetic ulcer wound fluid matrix metalloproteinases (MMPs), tissue inhibitors of metalloproteinases (TIMPs), and transforming growth factor-ß1 (TGF-ß1) with wound healing rate.RESEARCH DESIGN AND METHODS -The ulcers were cleansed to remove exudates, and wound fluids were collected for analysis of MMP-2 and -9, TIMP-1, and TGF-ß1.RESULTS -At presentation, MMP-9 and the MMP-9 -to-TIMP-1 ratio correlated inversely with the wound healing rate at 28 days (P Ͻ 0.001). MMP-9 and the MMP-9 -to-TIMP-1 ratio were lower in the 23 patients who achieved complete healing at 12 weeks versus the 39 who did not. The pro-MMP-9 concentration was predictive of healing within 12 weeks. Addition of cutoffs for TIMP-1 (Ͼ480 pg/ml) and TGF-ß (Ͼ115 pg/ml) further improved its predictive power (area under the curve 0.94).CONCLUSIONS -These findings suggest that a milieu with high MMP-9 may be indicative of inflammation and poor wound healing. Measurements of MMP-9, TIMP-1, and TGF-ß in wound fluid may help to identify ulcers at risk of poor healing.

Vascular reactivity is impaired in the systemic arteries of asymptomatic young adults with insulin-dependent diabetes and may represent early large-vessel disease. The degree of impairment is related to the duration of diabetes, and these patients appear particularly vulnerable to damage from LDL cholesterol, even at levels considered acceptable in nondiabetic subjects.

OBJECTIVE -Many individuals with diabetes experience neuropathic pain, often without objective signs of large-fiber neuropathy. We examined intraepidermal nerve fibers (IENFs) to evaluate the role of small nerve fibers in the genesis of neuropathic pain.RESEARCH DESIGN AND METHODS -Twenty-five diabetic subjects with neuropathic pain and 13 without were studied. The pain was present for at least 6 months for which no other cause could be found. Punch skin biopsies were obtained from the distal leg. IENFs were stained using antibody to protein gene product 9.5 and counted with confocal microscopy. Neuropathy was graded by vibration perception and cold detection thresholds and the Michigan Neuropathy Screening Instrument.RESULTS -In the total cohort, IENF density was significantly lower in those with pain compared with those without (3 [1-6] vs. 10 [3-19], respectively, P ϭ 0.02). There were significant inverse correlations between IENF and severity of neuropathy, with the pain group having a flatter gradient than their pain-free counterparts (P Ͻ 0.02). The difference in IENF density was greatest in subjects with less objective evidence of neuropathy (P Յ 0.01).CONCLUSIONS -More severe loss of IENF is associated with the presence of neuropathic pain only in those with little or no objective sign of neuropathy. Thus, loss of IENF cannot explain pain in all cases, suggesting that different mechanisms underpin the genesis of pain at various stages of neuropathy. Diabetes Care 29:883-887, 2006P eripheral neuropathy is a common complication of both type 1 and type 2 diabetes (1). Most commonly, it manifests as sensory loss, which predisposes subjects to foot abnormalities and high risk of ulceration. However, it has been reported that between 4 and 33% of subjects with diabetes suffer from the painful type of neuropathy, which can become chronic and produce unremitting pain for which there is little satisfactory treatment (2-4).It is known that pain transmission in peripheral nerves occurs along the small A␦ and C-type fibers (5,6). However, conventional clinical investigation of individuals with painful diabetic neuropathy is usually limited to nerve conduction studies that measure large-nerve fiber function. The results of these tests are often normal and unable to provide an explanation for the presence of pain (7,8). This conundrum reflects a common clinical observation that pain is often present in the absence of objective signs of neuropathy. Even in the presence of abnormal nerve conduction studies, some individuals may experience pain while others with the same degree of electrophysiological abnormalities are completely asymptomatic. It is commonly assumed that more specific testing of small-fiber function may better discriminate those with or without pain, but several studies, including our own, have shown this not to be the case (9 -11). However, in view of the pivotal role played by small nerve fibers in the transmission of pain sensation, further studies are obviously of importance.Direct examination of int...

In the majority of patients with diabetes, assessment of TBI conveys no advantage over ABI in determining perfusion pressure of the lower limbs. Only in those patients with overt calcification, which gives an ABI > or = 1.3, are toe pressure measurements superior. This guideline should simplify assessment and treatment of diabetic patients with disease of the lower limbs. Diabet. Med. 18, 528-532 (2001)

OBJECTIVEThis study compared the prevalence of complications in 354 patients with T2DM diagnosed between 15 and 30 years of age (T2DM [15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30] ) with that in a durationmatched cohort of 1,062 patients diagnosed between 40 and 50 years (T2DM [40][41][42][43][44][45][46][47][48][49][50] ). It also examined standardized mortality ratios (SMRs) according to diabetes age of onset in 15,238 patients covering a wider age-of-onset range. RESEARCH DESIGN AND METHODSComplication status was assessed according to a standard protocol and extracted from our electronic database. Survival status was ascertained by data linkage with the Australian National Death Index. SMRs were calculated in comparison with the background Australian population and analyzed according to age of onset. RESULTSAfter matching for duration, despite their younger age, T2DM 15-30 had more severe albuminuria (P = 0.004) and neuropathy scores (P = 0.003). T2DM 15-30 were as commonly affected by metabolic syndrome factors as T2DM 40-50 but less frequently treated for hypertension and dyslipidemia (P < 0.0001). An inverse relationship between age of diabetes onset and SMR was seen, which was the highest for T2DM 15-30 (3.4 [95% CI 2.7-4.2]). SMR plots adjusting for duration show that for those with T2DM 15-30 , SMR is the highest at any chronological age, with a peak SMR of more than 6 in early midlife. In contrast, mortality for older-onset groups approximates that of the background population. CONCLUSIONSThe negative effect of diabetes on morbidity and mortality is greatest for those diagnosed at a young age compared with T2DM of usual onset. These results highlight the growing imperative to direct attention toward young-onset T2DM and for effective interventions to be applied before middle age.Type 2 diabetes is well recognized to be a heterogeneous disorder, and its effect on morbidity and mortality may not be identical within this diagnosis. No longer just a disorder of mature age, there is now a well-recognized trend toward younger people presenting with this disease, particularly for some ethnic groups. Adolescents accounted for less than 4% of incident type 2 diabetes cases in the U.S. 15 years ago, but in a more