PO135 GLUCOSE-DEPENDENT INSULINOTROPIC POLYPEPTIDE (GIP) IS INVOLVED IN INAPPROPRIATE GLUCAGON SECRETION IN RESPONSE TO ORAL GLUCOSE LOADING IN TYPE 2 DIABETES

The study included 127 patients with type 2 diabetes (T2D) risk factors, who underwent oral glucose tolerance test (75 g glucose) with pancreatic and incretin hormones estimated in fasting state, at 30 and 120 minutes after glucose load. According to the test results the population was divided into 3 groups: group with normal glucose tolerance (NGT), group with high risk of diabetes developing (impaired glucose tolerance (IGT) and impaired fasting glycemia (IFG)) and newly-diagnosed T2D. The stimulated glucagon secretion was suppressed in NGT group, whereas in T2D patients there was an increase in glucagon levels at 30 min after the glucose load. Within high risk group the area under curve (AUC) of glucagon secretion was significantly elevated in IFG patients comparing to IGT (0,52 vs 0,07 ng·ml-1·min-1, р=0,0005). AUC of glucagon secretion was positively related only to fasting glucagon-like peptide 2 (GLP-2) level (r=0,61, р=0,0001), that suggests glucagonotropic properties for GLP-2. We conclude that glucagon stimulation by GLP-2 may play a role in decreased glucagon suppression in T2D patients and IFG state development.

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The separate and combined impact of the intestinal hormones, GIP, GLP-1, and GLP-2, on glucagon secretion in type 2 diabetes

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00665.2010 ◽

2011 ◽

Vol 300 (6) ◽

pp. E1038-E1046 ◽

Cited By ~ 95

Author(s):

Asger Lund ◽

Tina Vilsbøll ◽

Jonatan I. Bagger ◽

Jens J. Holst ◽

Filip K. Knop

Keyword(s):

Type 2 Diabetes ◽

Glucagon Secretion ◽

Tolerance Test ◽

Oral Glucose ◽

Intestinal Hormones ◽

Intravenous Glucose ◽

Glucagon Suppression ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

Type 2 diabetes mellitus (T2DM) is associated with reduced suppression of glucagon during oral glucose tolerance test (OGTT), whereas isoglycemic intravenous glucose infusion (IIGI) results in normal glucagon suppression in these patients. We examined the role of the intestinal hormones glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), and glucagon-like peptide-2 (GLP-2) in this discrepancy. Glucagon responses were measured during a 3-h 50-g OGTT ( day A) and an IIGI ( day B) in 10 patients with T2DM [age (mean ± SE), 51 ± 3 yr; body mass index, 33 ± 2 kg/m2; HbA1c, 6.5 ± 0.2%]. During four additional IIGIs, GIP ( day C), GLP-1 ( day D), GLP-2 ( day E) and a combination of the three ( day F) were infused intravenously. Isoglycemia during all six study days was obtained. As expected, no suppression of glucagon occurred during the initial phase of the OGTT, whereas significantly ( P < 0.05) lower plasma levels of glucagon during the first 30 min of the IIGI ( day B) were observed. The glucagon response during the IIGI + GIP + GLP-1 + GLP-2 infusion ( day F) equaled the inappropriate glucagon response to OGTT ( P = not significant). The separate GIP infusion ( day C) elicited significant hypersecretion of glucagon, whereas GLP-1 infusion ( day D) resulted in enhancement of glucagon suppression during IIGI. IIGI + GLP-2 infusion ( day E) resulted in a glucagon response in the midrange between the glucagon responses to OGTT and IIGI. Our results indicate that the intestinal hormones, GIP, GLP-1, and GLP-2, may play a role in the inappropriate glucagon response to orally ingested glucose in T2DM with, especially, GIP, acting to increase glucagon secretion.

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Cinammon (Cinnamomum Spp.) and Type 2 Diabetes Mellitus

Current Topics in Nutraceutical Research ◽

10.37290/ctnr2641-452x.18:247-255 ◽

2019 ◽

Vol 18 (3) ◽

pp. 247-255

Author(s):

Sierra-Puente D. ◽

Abadi-Alfie S. ◽

Arakanchi-Altaled K. ◽

Bogard-Brondo M. ◽

García-Lascurain M. ◽

...

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Systematic Reviews ◽

Meta Analysis ◽

Fasting Blood Glucose ◽

Tolerance Test ◽

Oral Glucose ◽

Key Aspects

Spices such as cinnamon (Cinnamomum Spp.) have been of interest due to their phytochemical composition that exert hypoglycemic effects with potential for management of type 2 diabetes mellitus (T2DM). We summarize data from 27 manuscripts that include, one book chapter, 3 review articles, 10 randomized controlled trials, 4 systematic reviews with meta-analysis, and 9 preclinical studies. The most frequently used cinnamon variety was Cinnamomum cassia rather than the Cinnamomum zeylanicum, whereas outcomes were defined as fasting blood glucose, glycated hemoglobin, and oral glucose tolerance test. A great variability in methodology such as different doses (from 120 mg to 6 g), duration of intervention, data retrieved and use of different concomitant medication, were found to be key aspects of most of trials and systematic reviews with meta-analysis available to date. Low quality studies have been made in most cases with a lot of heterogeneity clouding significance of results. More research needs to be done in order to yield accurate evidence for evidence-based recommendations. Its use is not currently a reliable nor advisable option for the treatment of T2DM.

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Skin autofluorescence predicts new cardiovascular disease and mortality in people with type 2 diabetes

BMC Endocrine Disorders ◽

10.1186/s12902-020-00676-4 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Henderikus E. Boersma ◽

Robert P. van Waateringe ◽

Melanie M. van der Klauw ◽

Reindert Graaff ◽

Andrew D. Paterson ◽

...

Keyword(s):

Blood Pressure ◽

Type 2 Diabetes ◽

Cardiovascular Disease ◽

Fasting Blood Glucose ◽

Multivariable Analysis ◽

Oral Glucose ◽

Skin Autofluorescence ◽

Z Score

Abstract Background Skin autofluorescence (SAF) is a non-invasive marker of tissue accumulation of advanced glycation endproducts (AGE). Recently, we demonstrated in the general population that elevated SAF levels predict the development of type 2 diabetes (T2D), cardiovascular disease (CVD) and mortality. We evaluated whether elevated SAF may predict the development of CVD and mortality in individuals with T2D. Methods We included 2349 people with T2D, available baseline SAF measurements (measured with the AGE reader) and follow-up data from the Lifelines Cohort Study. Of them, 2071 had no clinical CVD at baseline. 60% were already diagnosed with diabetes (median duration 5, IQR 2–9 years), while 40% were detected during the baseline examination by elevated fasting blood glucose ≥7.0 mmol/l) and/or HbA1c ≥6.5% (48 mmol/mol). Results Mean (±SD) age was 57 ± 12 yrs., BMI 30.2 ± 5.4 kg/m2. 11% of participants with known T2D were treated with diet, the others used oral glucose-lowering medication, with or without insulin; 6% was using insulin alone. Participants with known T2D had higher SAF than those with newly-detected T2D (SAF Z-score 0.56 ± 0.99 vs 0.34 ± 0.89 AU, p < 0.001), which reflects a longer duration of hyperglycaemia in the former group. Participants with existing CVD and T2D had the highest SAF Z-score: 0.78 ± 1.25 AU. During a median follow-up of 3.7 yrs., 195 (7.6%) developed an atherosclerotic CVD event, while 137 (5.4%) died. SAF was strongly associated with the combined outcome of a new CVD event or mortality (OR 2.59, 95% CI 2.10–3.20, p < 0.001), as well as incidence of CVD (OR 2.05, 95% CI 1.61–2.61, p < 0.001) and death (OR 2.98, 2.25–3.94, p < 0.001) as a single outcome. In multivariable analysis for the combined endpoint, SAF retained its significance when sex, systolic blood pressure, HbA1c, total cholesterol, eGFR, as well as antihypertensive and statin medication were included. In a similar multivariable model, SAF was independently associated with mortality as a single outcome, but not with incident CVD. Conclusions Measuring SAF can assist in prediction of incident cardiovascular disease and mortality in individuals with T2D. SAF showed a stronger association with future CVD events and mortality than cholesterol or blood pressure levels.

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Time to Failure on Oral Glucose-Lowering Agents for Patients with Type 2 Diabetes: A Retrospective Cohort Study

Diabetes Therapy ◽

10.1007/s13300-021-01051-9 ◽

2021 ◽

Author(s):

Kristina S. Boye ◽

Maureen J. Lage ◽

Jacek Kiljański

Keyword(s):

Type 2 Diabetes ◽

Cohort Study ◽

Retrospective Cohort Study ◽

Retrospective Cohort ◽

Oral Glucose ◽

Time To Failure ◽

Glucose Lowering

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Delayed initiation of subcutaneous insulin therapy after failure of oral glucose-lowering agents in patients with Type 2 diabetes: a population-based analysis in the UK

Diabetic Medicine ◽

10.1111/j.1464-5491.2007.02279.x ◽

2007 ◽

Vol 24 (12) ◽

pp. 1412-1418 ◽

Cited By ~ 89

Author(s):

A. Rubino ◽

L. J. McQuay ◽

S. C. Gough ◽

M. Kvasz ◽

P. Tennis

Keyword(s):

Type 2 Diabetes ◽

Insulin Therapy ◽

Population Based ◽

Oral Glucose ◽

Subcutaneous Insulin ◽

Glucose Lowering ◽

Delayed Initiation ◽

The Uk

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Structural Lesions on Kidney Biopsy in Youth-Onset and Adult-Onset Type 2 Diabetes

10.2337/figshare.17069885 ◽

2022 ◽

Author(s):

Helen C. Looker ◽

Laura Pyle ◽

Tim Vigers ◽

Cameron Severn ◽

Pierre Saulnier ◽

...

Keyword(s):

Type 2 Diabetes ◽

Kidney Disease ◽

Age Of Onset ◽

Tissue Injury ◽

Kidney Tissue ◽

Glomerular Sclerosis ◽

Oral Glucose ◽

Adult Onset ◽

Pima Indians

Objective: Type 2 diabetes (T2D) is a leading cause of end stage kidney disease (ESKD) worldwide. Recent studies suggest a more aggressive clinical course of diabetic kidney disease (DKD) in youth-onset than adult-onset T2D. We compared kidney structural lesions in youth- and adult-onset T2D to determine if youth-onset was associated with greater early tissue injury. Methods: Quantitative microscopy was performed on kidney tissue obtained from research kidney biopsies in 161 Pima Indians (117 women, 44 men) with T2D. Onset of T2D was established by serial oral glucose tolerance testing and participants were stratified as youth-onset (<25 years) or adult-onset (≥25 years). Associations between clinical and morphometric parameters and age of onset were tested using linear models. Results: At biopsy, the 52 participants with youth-onset T2D were younger than the 109 with adult-onset T2D (39.1±9.9 vs. 51.4±10.2 years, p<0.0001), but their diabetes duration was similar (19.3±8.1 vs. 17.0±7.8 years, p=0.09). Median urine albumin-to-creatinine ratio was higher in the youth-onset group (58 [25th-75th percentile, 17-470] vs. 27 [13-73] mg/g, p=0.02). Youth-onset participants had greater glomerular basement membrane (GBM) width (552±128 nm vs. 490±114nm, p=0.002) and mesangial fractional volume (0.31±0.10 vs. 0.27±0.08, p=0.001) than adult-onset participants. Percentage glomerular sclerosis, glomerular volume, mesangial fractional volume, and GBM width were also inversely associated with age of diabetes onset as a continuous variable. Conclusion: Younger age of T2D onset strongly associates with more severe kidney structural lesions. Studies are underway to elucidate the pathways underlying these associations.

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Are the metabolic benefits of resistance training in type 2 diabetes linked to improvements in adipose tissue microvascular blood flow?

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00234.2018 ◽

2018 ◽

Vol 315 (6) ◽

pp. E1242-E1250 ◽

Cited By ~ 1

Author(s):

Donghua Hu ◽

Ryan D. Russell ◽

Devika Remash ◽

Timothy Greenaway ◽

Stephen Rattigan ◽

...

Keyword(s):

Type 2 Diabetes ◽

Blood Flow ◽

Adipose Tissue ◽

Resistance Training ◽

Blood Volume ◽

Fasting Blood Glucose ◽

Microvascular Blood Flow ◽

Oral Glucose ◽

Model Assessment

The microcirculation in adipose tissue is markedly impaired in type 2 diabetes (T2D). Resistance training (RT) often increases muscle mass and promotes a favorable metabolic profile in people with T2D, even in the absence of fat loss. Whether the metabolic benefits of RT in T2D are linked to improvements in adipose tissue microvascular blood flow is unknown. Eighteen sedentary people with T2D (7 women/11 men, 52 ± 7 yr) completed 6 wk of RT. Before and after RT, overnight-fasted participants had blood sampled for clinical chemistries (glucose, insulin, lipids, HbA1c, and proinflammatory markers) and underwent an oral glucose challenge (OGC; 50 g glucose × 2 h) and a DEXA scan to assess body composition. Adipose tissue microvascular blood volume and flow were assessed at rest and 1 h post-OGC using contrast-enhanced ultrasound. RT significantly reduced fasting blood glucose ( P = 0.006), HbA1c ( P = 0.007), 2-h glucose area under the time curve post-OGC ( P = 0.014), and homeostatic model assessment of insulin resistance ( P = 0.005). This was accompanied by a small reduction in total body fat ( P = 0.002), trunk fat ( P = 0.023), and fasting triglyceride levels ( P = 0.029). Lean mass ( P = 0.003), circulating TNF-α ( P = 0.006), and soluble VCAM-1 ( P < 0.001) increased post-RT. There were no significant changes in adipose tissue microvascular blood volume or flow following RT; however those who did have a higher baseline microvascular blood flow post-RT also had lower fasting triglyceride levels ( r = −0.476, P = 0.045). The anthropometric, glycemic, and insulin-sensitizing benefits of 6 wk of RT in people with T2D are not associated with an improvement in adipose tissue microvascular responses; however, there may be an adipose tissue microvascular-linked benefit to fasting triglyceride levels.

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Paracrine control of α-cell glucagon exocytosis is compromised in human type-2 diabetes

10.1101/789545 ◽

2019 ◽

Author(s):

Muhmmad Omar-Hmeadi ◽

Per-Eric Lund ◽

Nikhil R Gandasi ◽

Anders Tengholm ◽

Sebastian Barg

Keyword(s):

Type 2 Diabetes ◽

Glucagon Secretion ◽

Cellular Level ◽

Membrane Excitability ◽

Granule Exocytosis ◽

Paracrine Effects ◽

Voltage Dependent ◽

Resolution Imaging ◽

Glucose Sensitivity

AbstractGlucagon is secreted from pancreatic α-cells to activate gluconeogenesis and other pathways that raise blood glucose during hypoglycemia. Glucose-dependent regulation of glucagon secretion involves both α-cell-intrinsic mechanisms and paracrine control through insulin and somatostatin. In type-2 diabetes (T2D) inadequately high glucagon levels contribute to hyperglycemia. To understand these disease-associated changes at the cellular level, and to isolate intrinsic and paracrine effects, we analyzed glucagon granule exocytosis and membrane excitability in isolated α-cells from 56 non-diabetic (ND) and 15 T2D human donors. High resolution imaging showed that glucagon granule exocytosis had a U-shaped sensitivity to glucose, with the slowest rate around 7 mM glucose, and accelerated rates at <5 and >10 mM glucose. Exocytosis was reduced in T2D α-cells, but their glucose sensitivity remained intact and there were no changes in voltage-dependent ion currents or granule trafficking. Instead, α-cells from T2D donors were markedly insensitive to somatostatin and insulin, which rapidly inhibited exocytosis and electrical activity in ND cells. Thus, intrinsic mechanisms do not inhibit glucagon secretion at hyperglycemia, and elevated glucagon levels in human T2D reflect an insensitivity of α-cells to paracrine inhibition.

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Interplay of Dinner Timing and MTNR1B Type 2 Diabetes Risk Variant on Glucose Tolerance and Insulin Secretion: A Randomized Crossover Trial

10.2337/figshare.17122142 ◽

2022 ◽

Author(s):

Marta Garaulet ◽

Jesus Lopez-Minguez ◽

Hassan S Dashti ◽

Céline Vetter ◽

Antonio Miguel Hernández-Martínez ◽

...

Keyword(s):

Type 2 Diabetes ◽

Insulin Secretion ◽

Glucose Tolerance ◽

Area Under The Curve ◽

Serum Levels ◽

Postprandial Glucose ◽

Oral Glucose ◽

Elevated Concentration ◽

Endogenous Melatonin

Objective: We tested whether the concurrence of food intake and elevated concentration of endogenous melatonin, as occurs in late eating, results in impaired glucose control, in particular in carriers of the type 2 diabetes-associated G allele in the melatonin-receptor-1-b gene (MTNR1B). Research Design and Methods: In a Spanish natural late eating population, a randomized, cross-over study design was performed, following an 8-h fast. Each participant (n=845) underwent two evening 2-h 75g oral glucose tolerance tests (OGTT): an early condition scheduled 4 hours prior to habitual bedtime (“early dinner-timing”), and a late condition scheduled 1 hour prior to habitual bedtime (“late dinner-timing”), simulating an early and a late dinner timing, respectively. Differences in postprandial glucose and insulin responses were determined using incremental area under the curve (AUC) calculated by the trapezoidal method between early and late dinner-timing. Results: Melatonin serum levels were 3.5-fold higher in the late vs. early condition, with late dinner-timing resulting in 6.7% lower insulin area-under-the-curve (AUC) and 8.3% higher glucose AUC. In the late condition MTNR1B G-allele carriers had lower glucose tolerance than non-carriers. Genotype differences in glucose tolerance were attributed to reductions in β-cell function (Pint AUCgluc=0.009, Pint CIR=0.022, Pint DI=0.018). Conclusions: Concurrently high endogenous melatonin and carbohydrate intake, as typical for late eating, impair glucose tolerance, especially in MTNR1B G-risk-allele carriers, attributable to insulin secretion defects.

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